Bioequivalence Evaluation of Generic Febuxostat versus Feburic ® in Healthy Chinese Subjects: A Randomized Crossover Study

Bioequivalence Evaluation of Generic Febuxostat versus Feburic ® in Healthy Chinese Subjects: A Randomized Crossover Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Bioequivalence Evaluation of Generic Febuxostat versus Feburic ® in Healthy Chinese Subjects: A Randomized Crossover Study Fengling Wang, Xi Ye, Fan Li, Hulin Kong, Minjie Liao, Min Kan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6492168/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Oct, 2025 Read the published version in BMC Pharmacology and Toxicology → Version 1 posted 12 You are reading this latest preprint version Abstract Purpose Febuxostat, a xanthine oxidase inhibitor, is a first-line treatment for gout with hyperuricemia. This study evaluated the pharmacokinetic (PK) bioequivalence, safety profile, and food effects of a generic febuxostat formulation compared to the reference product (Feburic®) in healthy Chinese volunteers Patients and Methods In this randomized, open-label, two-sequence, two-period crossover trial, 80 participants (74 males, 6 females) received single 40 mg doses of both test and reference formulations under fasting and fed conditions, separated by a 7-day washout. Plasma concentrations were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Primary endpoints included peak plasma concentration (C max ), area under the plasma concentration-time curve from time zero to the last time quantifiable time point (AUC 0 − t ), and area under the plasma concentration-time curve from time zero to infinity (AUC 0−∞ ), with bioequivalence determined using 90% confidence intervals (CIs) for geometric mean ratios (GMRs). Results All 90% CIs for GMRs fell within the 80–125% bioequivalence range (fasting: AUC 0 − t 99.08-104.28%, AUC 0−∞ 98.73-103.84%, C max 92.87-112.14%; fed: AUC 0 − t 101.16-106.21%, AUC 0−∞ 101.13-105.94%, C max 91.72-105.07%). High-fat meals delayed T max by 0.67 h ( P < 0.05) and reduced systemic exposure (C max by ~ 35%, AUC 0−∞ by ~ 12%). Adverse event incidence was 12.8% (fasting) and 25.0% (fed), with no serious adverse events reported. Conclusion The generic febuxostat formulation demonstrated PK equivalence to Feburic® under both fasting and fed conditions, with comparable safety profiles. The observed food effects, while statistically significant, support flexible administration without meal restrictions, positioning this generic as a clinically equivalent, cost-effective alternative for gout management. Clinical Trial Registration: This study was prospectively registered (Registration No. CTR20233483; First Public Release Date: 1 November 2023) in the Chinese Clinical Trial Registration Platform (http://www.chinadrugtrials.org.cn), a registry recognized by the Chinese National Medical Products Administration (NMPA). The trial was conducted from 28 November 2023 to 26 December 2023. febuxostat bioequivalence pharmacokinetics food effect generic drug Figures Figure 1 Figure 2 Figure 3 Introduction Xanthine oxidase inhibitors, represented by allopurinol and febuxostat, constitute the primary pharmacological approach for reducing uric acid production. Although allopurinol has been widely used since the 1960s, its potential for severe adverse reactions, including Stevens-Johnson syndrome, limits its use in patients with renal impairment [ 1 , 2 ]. In contrast, febuxostat, as a novel non-purine selective inhibitor targeting both oxidized and reduced forms of xanthine oxidase, offers comparable urate-lowering efficacy with superior safety, especially for patients with mild-to-moderate renal dysfunction [ 1 , 2 ]. Following its initial development in Japan (2004), febuxostat received successive approvals from the EMA (2008), FDA (2009), and the China National Food and Drug Administration (CFDA) (2013) [ 1 ]. In China, the recommended daily doses are 40 mg or 80 mg, with the brand-name product Feburic® (Teijin Pharma Limited) available as 20 mg and 40 mg tablets [ 3 ]. The development of generic febuxostat formulations meets a critical need for affordable urate-lowering therapies. Bioequivalence studies serve as the regulatory standard for demonstrating therapeutic equivalence, comparing key pharmacokinetic (PK) parameters including maximum plasma concentration (C max ), an indicator of absorption rate, and area under the plasma concentration-time curve (AUC), which reflects absorption extent. Regulatory approval requires that the 90% confidence intervals (CIs) for geometric mean ratios (GMRs) of these parameters fall within the 80–125% equivalence range [ 4 – 6 ]. In this context, our test formulation represents a cost-effective alternative to the reference product Feburic® (Teijin Pharma Limited). As a bioequivalent agent approved by regulatory authorities, it provides comparable PK performance while enhancing treatment accessibility for gout patients in China. Existing PK studies have documented febuxostat disposition in various populations, including Chinese subjects [ 7 , 8 ]. While comparative analyses demonstrate ethnic variations between Chinese and Caucasian populations [ 9 ], and a single-dose study showed comparable fasting-state profiles in Chinese males [ 7 ], critical knowledge gaps persist regarding food effects and gender differences in Chinese individuals [ 10 ]. Population PK (PopPK) modeling reveals food reduces febuxostat bioavailability by 67% in this population [ 11 ], with multi-peak absorption patterns observed across ethnic groups [ 12 , 13 ]. To address these evidence gaps, we conducted a randomized, single-dose, open-label, two-sequence crossover study comparing a 40 mg test formulation (Hubei Biocause Heilen Pharmaceutical) with Feburic® in healthy Chinese volunteers of both sexes under fasting and fed conditions. This dual-state design enables comprehensive characterization of both the fasted and fed PK profiles while accounting for the established food effects and absorption variability in the target population. Material and methods Study Materials The test formulation (T) of febuxostat tablets (40 mg; batch no. 20230803) was produced and provided by Hubei Biocause Heilen Pharmaceutical Co., Ltd. Reference product (R, Feburic®; 40 mg; batch no. 4221B) was sourced from original manufacturer (Teijin Pharma Limited, Japan), ensuring traceability. Analytical standards included febuxostat reference substance (99.4% purity; batch no. 4326-005A1) and the internal standard febuxostat-d7 (97.9% purity; batch no. 4296-093A3), both obtained from TLC Pharmaceutical Standards. All solvents were HPLC grade, including ultrapure water, acetonitrile, methanol, formic acid, and ammonium acetate. Subjects Healthy Chinese volunteers who met all inclusion criteria were enrolled in this study after providing written informed consent. Eligible participants included males and females aged ≥ 18 years with body mass index (BMI) between 19.0 and 26.0 kg/m 2 (inclusive), with minimum body weights of 50.0 kg for males and 45.0 kg for females. All subjects demonstrated normal or clinically insignificant results in physical examinations (including vital signs), electrocardiograms, chest X-rays, and laboratory tests (hematology, biochemistry, and urinalysis). Female participants of childbearing potential agreed to use effective contraception from 30 days before consent until 90 days after the final study drug administration and had no immediate pregnancy plans. Exclusion criteria included: serum uric acid levels ≥ 1.2 times the upper limit of normal; history of significant chronic illness or allergic conditions; recent use of medications or health supplements (within 14 days) or planned vaccinations (within 28 days post-study); major surgery within the past year or planned during the study; participation in other clinical trials within 90 days; smoking ≥ 5 cigarettes/day or inability to abstain during the study; alcohol consumption > 14 units/week or positive alcohol breath test; and current pregnancy or breastfeeding status. Study Design, Ethics, and Randomization This randomized, open-label, single-dose, two-sequence, two-period crossover study was conducted at the Phase I Clinical Trial Center of Hefei Hospital Affiliated to Anhui Medical University (The Second People’s Hospital of Hefei). The study protocol was approved by the Clinical Trial Ethics Committee of The Second People’s Hospital of Hefei (Approval No. 2023 Ethical Opinion-Medical-037-01) and registered (CTR20233483) at the Chinese Clinical Trial Registration Platform ( http://www.chinadrugtrials.org.cn/index.html ), complying with the Declaration of Helsinki [ 14 ], ICH-GCP guidelines [ 15 ], and China National Medical Products Administration (NMPA) regulations. The execution dates of the study were from November 28, 2023, to December 26, 2023. Sample size determination was based on China NMPA data showing intra-individual variability for febuxostat tablets (C max : 7.29–37.02%; AUC 0 − t : 5.86–20.49%; AUC 0−∞ : 5.93–7.83%). Using PASS 11.0 software with α = 0.05, power = 80%, and GMR = 0.95, we calculated that 31 evaluable subjects per group would provide adequate statistical power. Accounting for potential 20% dropout, we enrolled 40 subjects per group (80 total). Randomization employed a block design (size = 4) generated using SAS® 9.4 (PROC PLAN; fixed seed = 517393506), with subjects allocated to either TR (test→reference) or RT (reference→test) sequences and a 7-day washout between periods. While the study was open-label, bioanalysts remained blinded to treatment sequences during PK analysis. In the fasting condition, participants fasted ≥ 10 h before receiving a single 40 mg dose with 240 mL water. For the fed condition, subjects consumed a standardized high-fat meal (800–1000 kcal; 50% fat, 15% protein, 25% carbohydrates) 30 minutes before dosing. Water intake was restricted 1 h pre- and post-dose, with standardized meals provided at 4 h and 10 h post-dose. All protocol deviations were documented and reported to the Ethics Committee. Blood Sampling and Processing PK blood samples (4 mL each) were collected in K 2 -EDTA anticoagulant tubes (Jiangsu YuLi Medical Instrument Co., Ltd) in each stage (pre-dose and at 10 min, 20 min, 40 min, 1 h, 1 h 20 min, 1 h 40 min, 2 h, 2 h 20 min, 2 h 40 min, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 36 h after administration under fasting condition; pre-administration and at 10 min, 20 min, 40 min, 1 h, 1 h 20 min, 1 h 40 min, 2 h, 2 h 20 min, 2 h 40 min, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 36 h after administration under fed condition). The plasma samples were centrifuged (2000 g, 10 min, 4°C) within 60 min, and the plasma separated was stored at -80°C until PK analysis. PK analysis A validated, specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was employed to analyze the plasma concentration of febuxostat in human. Waters Acquity (Waters Corporation, Milford, Massachusetts) and Sciex API 6500 Triple Quad mass spectrometer Applied Biosystem with an electrospray ionization source were combined for the LC-MS/MS analysis. ExionLC and Sciex ExionLC API 6500 + Triple Quad mass spectrometer Applied Biosystem (Applied Biosystems/Sciex, USA) with an electrospray ionization source were combined for the LC-MS/MS analysis. Febuxostat-d7 was used as an internal standard. The linear range is 5.00 ~ 5000 ng/mL for febuxostat. The lower limit of quantification was 5.00 ng/mL. The maximum precision (CV%) of the quality control sample was 3.5%. The accuracy bias (%) from the theoretical concentration of the quality control samples was between 1.2% and 5.7%. The analytes in the plasma maintained their stability after storage at room temperature for 28 h. Similarly, the analytes in the treated plasma samples remained stable even after storage at 4℃ for 237 h and in an automatic sampler for 196 h. Furthermore, the analytes in plasma remain stable even after being stored at -20℃ and − 80℃ for 13 days and 49 days, respectively. The plasma samples were placed at -20℃ and − 80℃ for five freeze-thaw cycles remained stable. Chromatographic separation employed an ACE Excel 3 SuperC 18 column (50 mm×2.1 mm, 3 µm). The mobile phases A (10 mM ammonium acetate containing 0.1% formic acid) and B (acetonitrile) were eluted using a gradient, with a flow rate of 0.3 mL/min, a starting ratio of 45% for pump B, an injection volume of 2.0 µ L, and the column temperature was set to 40℃. Quantitative analysis of febuxostat and its internal standard (febuxostat-d7) was performed using electrospray ionization (ESI) in positive ion mode. The mass spectrometer was operated with the following optimized parameters: ion spray voltage of + 5500 V, source temperature of 500℃, collision gas (N2) pressure of High, spray gas (N2) pressure of 55 psi, air curtain gas (N2) pressure of 25 psi, and entrance potential of 10 V. Quantitation was performed by monitoring the transitions at m/z 317.3→m/z 261.1 for febuxostat and m/z 324.2→m/z 262.1 for febuxostat-d7. The dwell time was set to 150 ms. Ionization mode was electric spray ionization source and positive ion condition scanning, and scanning mode was multi reaction ion monitoring mode. Safety Analysis The safety of febuxostat tablet was evaluated based on observation of adverse events (AEs), vital signs (temperature, blood pressure, and pulse), laboratory tests (hematology, biochemistry, urinalysis, coagulation function, and blood pregnancy), physical examination, and electrocardiography. Vital signs were monitored in each stage (pre-administration and at 2 h, 6 h, 12 h, 24 h, and 36 h after administration for both fasting group and fed group). Other examinations were conducted at screening and early exit or removal from the study. AEs were monitored throughout the study and all recorded AEs were graded according to the National Cancer Institute Common Terminology Criteria for AEs (CTCAE 5.0 graded). All AEs were followed up until elimination or stabilization of the events. PK and Statistical Analysis PK parameters were calculated using non-compartmental analysis with Phoenix WinNonlin software (version 8.0, Certara Inc., Princeton, NJ, USA). Analysis of variance (ANOVA) was performed for significance test. In the analysis of variance model, the administration order, formulation, and period were used as fixed effects, while the subjects (order) are used as random effects. The statistical significance of differences between administration sequences, formulations, and cycles was analyzed by SAS 9.4 (SAS Institute Inc., Cary, NC, USA), with a significance level of α = 0.05. The major PK parameters included C max , AUC 0 − t , and AUC 0−∞ . The secondary PK parameters included the time of the maximum plasma concentration (T max ) and terminal half-life ( t 1/2 ) of febuxostat in plasma were also measured. These parameters were described as mean value (mean) and standard deviation (SD). After performing natural logarithmic transformation on PK parameters using a bioequivalence dataset, variance analysis was first performed, and then bioequivalence evaluation was performed using CI method. After a natural logarithmic conversion, the 90% CIs of GMRs (T/R) were calculated. The two formulations was considered to bioequivalent if 90% CIs fell within 80.00%-125.00% for AUC 0 − t , AUC 0− ∞ , and C max . AEs that occurred in this study will be statistically described based on incidence, severity, and correlation analysis between AEs and the study drug. Results Subject characteristics A total of 153 volunteers were screened, with 80 Han Chinese subjects enrolled (40 in each fasting and fed group). Demographic characteristics were comparable between groups (Table 1), including age, height, weight, and BMI ( P >0.05). In the fasting group, 40 participants (36 males, 4 females) were randomized, with 38 completing the study. One subject withdrew before the first cycle, and the other only completed the first cycle. In the fed group, all 40 participants (38 males, 2 females) randomized and successfully completed the trial. The study design is summarized in Fig. 1. Overall, 79 subjects were included in the PK concentration set, PK parameter set, bioequivalence analysis set, safety analysis set, and full analysis set. Table 1 Demographic Characteristics of participants in the Fasting and Fed Studies Characteristics Fasting Fed Sequence A (R-T) (n=20) Sequence B (T-R) (n=20) Total (n=40) P Sequence A (R-T) (n=20) Sequence B (T-R) (n=20) Total (n=40) P Age(years) 0.966 0.494 Mean±SD 27.55±6.79 27.65±7.84 27.60±7.24 29.15±5.96 30.60±7.26 29.88±6.60 Median 28.0 28.0 28.0 31.00 29.50 30.0 Min, Max 18.0, 48.0 19.0, 47.0 18.0, 48.0 19.0, 40.0 19.0, 45.0 19.0, 45.0 Height(cm) 0.242 0.897 Mean±SD 167.23±5.75 169.33±5.41 168.28±5.61 170.45±4.67 170.18±8.20 170.31±6.59 Median 166.50 170.75 168.75 170.50 170.75 170.50 Min, Max 155.5, 180.0 159.0, 177.0 155.50, 180.0 160.50, 179.0 149.0, 180.0 149.0, 180.0 Weight(kg) 0.127 0.228 Mean±SD 62.82±6.90 66.45±7.78 64.63±7.49 65.48±6.94 68.51±8.63 66.99±7.88 Median 62.85 67.80 64.95 64.95 70.80 66.75 Min, Max 52.10, 76.20 50.20,76.80 50.20, 76.80 55.10, 79.20 53.60, 80.10 53.60, 80.10 BMI(kg/m 2 ) 0.238 0.105 22.43±1.81 23.12±1.83 22.43±1.81 22.53±2.08 23.61±2.01 23.07±2.09 22.25 23.20 22.25 22.75 24.00 23.75 19.60, 25.90 19.90, 25.80 19.60, 25.90 19.20, 25.60 19.50, 26.0 19.20, 26.0 Abbreviations: BMI, body mass index; R, reference drug; T, test drug. PK results and bioequivalence evaluation Blood samples from all 79 subjects were analyzed. Linear and semi-logarithmic mean plasma drug concentration-time curves of febuxostat after single-dose administration of T and R formulations are shown in Fig. 2A/B (fasting) and Fig. 3A/B (fed). The curves for T and R overlapped closely under both conditions. Major PK parameters (Table 2) revealed comparable mean values for C max , AUC 0-t , and AUC 0-∞ between T and R, indicating similar PK profiles. Bioequivalence was confirmed, as all 90% CIs for GMRs fell within the 80.00-125.00% range (Table 3). No significant difference in T max were observed ( P >0.05), supporting consistent absorption rates and extents. Notably, C max values differed significantly between fasting and fed states, with postprandial values markedly lower than fasting values. Table 2 Pharmacokinetic Parameters of Febuxostat (Test vs. Reference) under fasting and fed conditions Parameter Fasting condition Fed condition Test (n=38) Reference (n=39) Test (n=38) Reference (n=39) T max (h) ■ 1 (0.33, 4.50) 1 (0.33, 4.51) 1.67 (0.67, 4.50) 1.5 (0.67, 5.0) C max (ng·mL -1 )* 2097.95±639.16 2067.513±723.51 1353.050±387.16 1400.225±486.14 AUC 0-t (ng·mL -1 ·h)* 6011.93±1918.58 5818.290±1851.30 5285.485±1321.48 5078.916±1198.94 AUC 0-∞ (ng·mL -1 ·h)* 6120.16±1930.87 5940.61±1845.62 5364.85±1329.66 5164.07±1216.21 λ z (h -1 )* 0.111±0.02 0.114±0.028 0.144±0.029 0.149±0.04 t 1/2 (h)* 6.463±1.26 6.448±1.64 5.036±1.153 4.978±1.28 Notes : ■ Values were presented as median (min, max); *Values were presented as mean ± SD (%CV). Abbreviations: AUC 0-t, area under the plasma concentration-time curve from time zero to the last measurable concentration;AUC 0-∞ , area under the plasma concentration-time curve from time zero to infinity; C max , maximum plasma concentration;T max , time to reach maximum plasma concentration; λ z ,Terminal elimination rate constant; t 1/2 , elimination half-life. Table 3 Bioequivalence statistics for pharmacokinetic parameters Parameter Geometric mean and ratio (n = 39) CV (%) 90%CI Power (%) ANOVA p value # Test Reference (T/R)% Sequence Period Formulations Fasting C max (ng·mL -1 ) 1986.811 1946.915 102.05 24.78 92.87-112.14 96.80 0.387 0.371 0.718 AUC 0-t (ng·mL -1 ·h) 5614.802 5523.815 101.65 6.62 99.08-104.28 >99.99 0120 0.889 0.288 AUC 0-∞ (ng·mL -1 ·h) 5723.110 5652.396 101.25 6.52 98.73-103.84 >99.99 0123 0.748 0.411 Fed C max (ng·mL -1 ) 1301.433 1325.698 98.17 18.17 91.72-105.07 99.96 0.076 0.337 0.649 AUC 0-t (ng·mL -1 ·h) 5123.248 4942.635 103.65 6.46 101.16-106.21 >99.99 0.079 0.105 0.017 AUC 0-∞ (ng·mL -1 ·h) 5203.560 5027.266 103.51 6.18 101.13-105.94 >99.99 0.074 0.069 0.017 Notes : # ANOVA was performed on log-transformed parameters (lnAUC 0–t , lnAUC 0–∞ , lnC max ); P < 0.05 indicates statistical significance. Abbreviations: AUC 0-t, area under the plasma concentration-time curve from time zero to the last measurable concentration;AUC 0-∞ , area under the plasma concentration-time curve from time zero to infinity; CI, confidence interval; C max , maximum plasma concentration; CV, coefficient of variation; R, reference drug; T, test drug. Safety results In the fasting group, a total of 6 AEs were reported among 5 subjects in the fasting group, yielding an AE incidence rate of 12.8% (5/39 subjects). Among these, 5 AEs in 4 subjects were assessed as "likely related" to the study drug, while 1 AE in 1 subject was deemed "possibly related", collectively classified as adverse drug reactions (ADRs) with an ADR incidence rate of 12.8%. All AEs were Grade 1 (mild) in severity, and no serious adverse events (SAEs) occurred (Table 4). In the fed group, 13 AEs were reported among 10 subjects, corresponding to an AE incidence rate of 25.0% (10/40 subjects). Of these, 13 AEs (in 10 subjects) were categorized as "possibly related" or "very likely related" to the investigational drug, resulting in an ADR incidence rate of 25.0%. One AE was Grade 2 (moderate), while the remainder were Grade 1; no SAEs were observed (Table 4). Table 4 Summary of adverse events Fasting Fed Test (n=38) Reference (n=39) Total, n (%) Test (n=40) Reference (n=40) Total, n (%) Instance n (%) Instance n (%) Instance n (%) Instance n (%) Total AEs 4 3(7.7%) 2 2(5.1%) 5(12.8%) 5 6(12.5%) 5 7(12.5%) 10(25%) AEs of grade 1 and above 4 3(7.7%) 2 2(5.1%) 5(12.8%) 5 6(12.5%) 5 6(12.5%) 10(25%) AEs of grade 2 0 0 0 0 0 0 0 1 1(2.5%) 1(2.5%) AEs of grade 3 and above 0 0 0 0 0 0 0 0 0 0 SAEs 0 0 0 0 0 0 0 0 0 0 AEs leading to exit 0 0 0 0 0 0 0 0 0 0 Notes : n (%) is the proportion of adverse drug reactions among all subjects taking febuxostat. Abbreviations : AEs, adverse events; SAE, serious adverse event; n, number of subjects; No subjects withdrew from the trial due to AEs, and all reported AEs resolved with recovery or remission. There were no unexpected AEs or ADRs. These findings demonstrate that both T and R formulations of febuxostat (40 mg) were well-tolerated and exhibited a favorable safety profile in healthy Chinese subjects under fasting and fed conditions. Discussion Since its FDA approval in 2009, febuxostat has demonstrated equivalent efficacy and tolerability in long-term management of hyperuricemia in gout patients, prompting significant interest in generic development [7]. The bioequivalence of the generic febuxostat supports its use as a cost-effective alternative, potentially improving medication access in resource-limited settings. The recommended initial dosage for oral administration of febuxostat tablets is 40 mg once daily, with potential escalation to 80 mg if serum uric acid remains >6 mg/dL (≈360 μmol/L) after two weeks [16]. Generic formulations offer substantial cost savings while maintaining therapeutic equivalence when bioequivalence is established. As a standard bioequivalence test, healthy male and female volunteers were commonly given preference, which could reduce the impact of individual and gender differences. In accordance with FDA guidelines for Feburic ® , the bioequivalence of the T and R should be evaluated under the fasting and fed states, respectively. There are indeed few bioequivalence studies on single dose administration of 40 mg febuxostat tablet by females. The published PK properties and bioequivalent results of febuxostat might be unsuitable for Chinese female volunteers under both fasting and fed states [7, 17, 18]. This randomized, single-dose, open-label, two-sequence crossover trial evaluated PK characteristics and bioequivalence of T versus R febuxostat (40 mg) in healthy Chinese volunteers under fasting and fed conditions. Notably, our study included both sexes, addressing a gap in existing literature where most bioequivalence data derive from male subjects. Study design followed FDA [19] and NMPA guidelines, with Teijin Pharma's Feburic ® selected as R based on NMPA's reference preparation standards. Methodologically, in accordance with FDA guidance on “Bioequivalence (BE) Studies with PK Endpoints for Drugs Submitted Under an ANDA” [20], we quantified febuxostat plasma concentrations (rather than metabolites) using a validated LC-MS/MS method [21, 22]. Demographic characteristics demonstrated no significant intergroup differences. Bioequivalence was established, with 90% CIs for GMRs of C max , AUC 0-t , and AUC 0-∞ falling within the 80-125% acceptance range under both fasting and fed conditions. Comparative analysis of T max showed no statistically significant formulation differences ( P >0.05). Our fasting-state PK parameters were consistent with previous reports [23], although observed AUC values were moderately elevated—a difference potentially explained by the inclusion of female participants (35 males:4 females) in our cohort. This finding corroborates established evidence of gender-related PK variations, wherein female subjects typically demonstrate higher C max and AUC values, likely attributable to body weight differences [8]. Interestingly, our values exceeded those reported in Caucasian populations [17, 24], corroborating reports of higher febuxostat exposure in Asians versus Caucasians, independent of body weight [17]. These ethnic PK variations underscore the importance of population-specific dosing considerations. Following oral administration of a single 40 mg dose, both T and R formulations demonstrated rapid absorption under fasting conditions, with median T max values of 1 h (range: 0.33-4.50 h) and 1 h (range: 0.33-4.51 h), respectively. Consistent with population PK models demonstrating 67% reduced bioavailability under fed conditions [11]. Previous studies have established that food effects primarily manifest as alterations in absorption rate and extent for orally administered medications [25]. Specifically, a PopPK study of febuxostat in healthy Chinese subjects demonstrated that concomitant high-fat meal consumption decreased both the absorption rate and bioavailability of febuxostat [10], which aligns precisely with our observations. In our fed cohort, absorption was moderately delayed compared to fasting conditions, with median T max values of 1.67 h (range: 0.67-4.5 h) and 1.5 h (range: 0.67-5 h) for T and R formulations, respectively. The observed reductions in systemic exposure under fed conditions—approximately 35% for C max , 12% for AUC 0-∞ , and 23% for t 1/2 —were consistent with the food effects described in Feburic ® prescribing information. Importantly, the effects of high-fat diet on both formulations showed comparable patterns, with 90% CIs for GMRs of all primary PK parameters (AUC 0-t , C max , and AUC 0-∞ ) falling within the 80-125% bioequivalence range. These results demonstrate that the generic formulation maintains similar absorption and elimination characteristics to the reference product regardless of prandial state, supporting its administration without strict meal timing requirements [26]. The safety profiles of the T and R formulations were comparable. Both formulations were well tolerated, with no SAEs observed. According to previous studies and the prescribing information for the reference drug, the most common AEs were mild and transient, including liver dysfunction, nausea, joint pain, rash, and dizziness (incidence >1%) [27, 28]. In our study, two subjects experienced ADRs of liver dysfunction (one each in fasting and fed groups), and one subject reported dizziness in the fasting group. Other common AEs described in the literature were not observed in our study, which may be related to the single-dose administration. Nevertheless, clinicians should remain vigilant for these potential AEs during febuxostat therapy. Three limitations warrant consideration: the single-dose design in healthy volunteers may not reflect chronic use patterns, the small female cohort (n=6) limits gender-specific conclusions, and the absence of patient populations requires confirmation of clinical outcomes. Further studies in gout patients and special populations (particularly renal impairment) are essential to fully establish therapeutic equivalence. These results nevertheless provide robust PK evidence supporting the generic's use while identifying key areas for future research. Conclusions This study provides robust pharmacokinetic evidence supporting the clinical application of a generic febuxostat formulation, demonstrating bioequivalence to the reference product (Feburic ® ) under both fasting and fed conditions in healthy Chinese subjects. The validated LC-MS/MS analytical method and randomized crossover design ensured reliable assessment of key pharmacokinetic parameters, all of which met regulatory bioequivalence criteria. These findings support the generic formulation as a therapeutically equivalent and cost-effective alternative for gout management, while highlighting the importance of considering food effects in clinical dosing regimens. Abbreviations ADR, adverse drug reaction; AE, adverse event; AUC, area under the curve; AUC 0-t, area under the plasma concentration-time curve from time zero to the last measurable concentration;AUC 0-∞ , area under the plasma concentration-time curve from time zero to infinity; BMI, body mass index; CI, confidence interval; C max , maximum plasma concentration; CV, coefficient of variation; FDA, US Food and Drug Administration; GCP, Good Clinical Practice; GMR, geometric mean ratio; HPLC, high performance liquid chromatography; ICH, International Council for Harmonisation; LC-MS/MS, liquid chromatography-tandem mass spectrometry; NMPA, National Medical Products Administration; PK, pharmacokinetic; PopPK, population pharmacokinetic; R, reference drug; SAE, serious adverse event; T, test drug; T max , time to reach maximum plasma concentration; t 1/2 , elimination half-life. Declarations Ethics approval and consent to participate The study passed the review of Clinical Trial Ethics Committee of The Second People’s Hospital of Hefei (Approval No. 2023 Ethical Opinion-Medical-037-01) . The written informed consents was obtained from all participants. Consent for publication Not applicable. Availability of data and materials Original data supporting the Conclusions of this study will be provided by the author (Fengling Wang) and should be retained. Competing interests The author(s) report no conflicts of interest in this work. Funding This study was supported by Hubei Biocause Heilen Pharmaceutical Co., Ltd. The funder was not involved in the study design, data collection, analysis, interpretation, article writing, or the decision to submit the manuscript for publication. Authors' contributions The study was designed by XYM and FLW. FLW, XY, FL and AGW performed the research. FLW. FLW, XY and FL wrote the paper. HLK, MJL, MK and JXZ participated in the acquisition of data and statistics. The author (s) gave final approval of the version to be published and agreed to be accountable for all aspects of the work. Acknowledgements We thank all enrolled participants, investigators, and individuals who contributed to this study. Authors' information (optional) 1 Phase I Clinical Trial Center, Hefei Hospital Affiliated to Anhui Medical University (The Second People’s Hospital of Hefei), Hefei 230011, Anhui Province, China. References Ernst ME, Fravel MA. Febuxostat: a selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout. Clin Ther. 2009;31(11):2503–2518. doi:10.1016/j.clinthera.2009.11.033 Becker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450–2461. doi:10.1056/NEJMoa050373 Zhou Q, Su J, Zhou T, et al. A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study. Int J Clin Pharmacol Ther. 2017;55(2):163–168. doi:10.5414/CP202629 Howland RH. Evaluating the bioavailability and bioequivalence of generic medications. J Psychosoc Nurs Ment Health Serv. 2010;48(1):13–16. doi:10.3928/02793695-20091204-07 Bhushan R, Martens J. Generic pharmaceuticals, regulatory aspects, bioequivalence investigation, and perception. Expert Opin Drug Saf. 2024;23(2):177–186. doi:10.1080/14740338.2024.2305709 US Food and Drug Administration. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Center for Drug Evaluation and Research (CDER); 2001. https://www.fda.gov/media/70858/download. Accessed 24 Jan, 2025. Luo Z, Nan F, Miao J, et al. Pharmacokinetics and bioequivalence of two formulations of febuxostat 40-mg and 80-mg tablets: a randomized, open-label, 4-way crossover study in healthy Chinese male volunteers. PLoS One. 2016;11(3):e0150661. doi:10.1371/journal.pone.0150661 Zhou H, Zheng Y, Wu G, et al. Pharmacokinetics and tolerability of febuxostat after oral administration in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose three-way crossover study. Int J Clin Pharmacol Ther. 2016;54(2):115–124. doi:10.5414/CP202394 Kamel B, Graham GG, Williams KM, et al. Clinical pharmacokinetics and pharmacodynamics of febuxostat. Clin Pharmacokinet. 2017;56(5):459–475. doi:10.1007/s40262-016-0466-4 Chen W, Jiang B, Ruan Z, et al. Population pharmacokinetic analysis of febuxostat with high focus on absorption kinetics and food effect. BMC Pharmacol Toxicol. 2024;25(1):57. doi:10.1186/s40360-024-00783-1 Kamel B, Abuhelwa AY, Foster D, et al. Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout. Br J Clin Pharmacol. 2022;88(12):5359-5368. doi:10.1111/bcp.15462 Wang C, Yu Q, Jiang X, et al. A drug-drug interaction study of a novel selective urate reabsorption inhibitor, SHR4640, and xanthine oxidase inhibitor, febuxostat, in patients with primary hyperuricemia. J Clin Pharmacol. 2023;63(2):239–249. doi:10.1002/jcph.2159 Grabowski B, Khosravan R, Wu JT, et al. Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase. Br J Clin Pharmacol. 2010;70(1):57–64. doi:10.1111/j.1365-2125.2010.03667.x World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191–2194. doi:10.1001/jama.2013.281053 International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed 24 Jan, 2025. Takeda Pharmaceuticals USA. ULORIC (febuxostat) Tablets Prescribing Information. US Food and Drug Administration; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021856s013lbl.pdf. Accessed 20 Jan, 2025. Rekić D, Johansson S, Leander J. Higher febuxostat exposure observed in Asian compared with Caucasian subjects independent of bodyweight. Clin Pharmacokinet. 2021;60(3):319–328. doi:10.1007/s40262-020-00943-6 Chandu BR, Kanala K, Hwisa NT, et al. Bioequivalence and pharmacokinetic study of febuxostat in human plasma by using LC-MS/MS with liquid-liquid extraction method. Springerplus. 2013;2:194. doi:10.1186/2193-1801-2-194 US Food and Drug Administration. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Center for Drug Evaluation and Research (CDER); 2022. https://www.fda.gov/media/70858/download. Accessed 22 Jan, 2025. US Food and Drug Administration. Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA. Center for Drug Evaluation and Research (CDER); 2021. https://www.fda.gov/media/87219/download. Accessed 20 Jan, 2025. Xu Y, Chen J, Yang D, et al. Development of LC-MS/MS determination method and backpropagation artificial neural networks pharmacokinetic model of febuxostat in healthy subjects. J Clin Pharm Ther. 2021;46(2):333–342. doi:10.1111/jcpt.13285 Wu Y, Mao Z, Liu Y, et al. Simultaneous determination of febuxostat and its three active metabolites in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study in Chinese healthy volunteers. J Pharm Biomed Anal. 2015;114:216–221. doi:10.1016/j.jpba.2015.05.020 Yu M, Li XB, Wang WP, et al. Pharmacokinetics study of single and multiple doses of febuxostat in Chinese healthy subjects [in Chinese]. Zhongguo Linchuang Yaolixue Zazhi [Chin J Clin Pharmacol]. 2023;39(5):723-727. doi:10.13699/j.cnki.1001-6821.2023.05.024 Khosravan R, Kukulka MJ, Wu JT, et al. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2008;48(9):1014–1024. doi:10.1177/0091270008322035 Deng J, Zhu X, Chen Z, et al. A review of food-drug interactions on oral drug absorption. Drugs. 2017;77(17):1833–1855. doi:10.1007/s40265-017-0832-z Khosravan R, Grabowski B, Wu JT, et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol. 2008;65(3):355–363. doi:10.1111/j.1365-2125.2007.03025.x Kamatani N, Fujimori S, Hada T, et al. Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011;17(4 Suppl):S19–S26. doi:10.1097/RHU.0b013e31821d36de Teijin Pharma Limited. Feburic ® (febuxostat) Tablets Prescribing Information. Tokyo, Japan; 2023. https://www.pmda.go.jp/PmdaSearch/iyakuSearch/. Accessed 20 Jan, 2025. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 06 Oct, 2025 Read the published version in BMC Pharmacology and Toxicology → Version 1 posted Editorial decision: Revision requested 05 Jun, 2025 Reviews received at journal 03 Jun, 2025 Reviews received at journal 21 May, 2025 Reviews received at journal 21 May, 2025 Reviewers agreed at journal 18 May, 2025 Reviewers agreed at journal 16 May, 2025 Reviewers agreed at journal 16 May, 2025 Reviewers invited by journal 16 May, 2025 Editor invited by journal 06 May, 2025 Editor assigned by journal 22 Apr, 2025 Submission checks completed at journal 22 Apr, 2025 First submitted to journal 20 Apr, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6492168","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":458185900,"identity":"01c5a444-15e4-46c3-906d-0836bd6cfa33","order_by":0,"name":"Fengling Wang","email":"","orcid":"","institution":"Hefei Hospital Affiliated to Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fengling","middleName":"","lastName":"Wang","suffix":""},{"id":458185901,"identity":"fd6a2f35-ccfb-49d3-86c2-204126ba0006","order_by":1,"name":"Xi Ye","email":"","orcid":"","institution":"Hefei Hospital Affiliated to Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xi","middleName":"","lastName":"Ye","suffix":""},{"id":458185902,"identity":"2f897288-a2a8-435f-8e03-3ff107dafbf5","order_by":2,"name":"Fan Li","email":"","orcid":"","institution":"Hefei Hospital Affiliated to Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"Li","suffix":""},{"id":458185903,"identity":"f4f3d5b7-ba14-4b9e-b2a3-4249a7cb69db","order_by":3,"name":"Hulin Kong","email":"","orcid":"","institution":"Hubei Biocause Heilen Pharmaceutical Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Hulin","middleName":"","lastName":"Kong","suffix":""},{"id":458185904,"identity":"37e2c548-2df3-43d5-8de9-445c452bf53a","order_by":4,"name":"Minjie Liao","email":"","orcid":"","institution":"Hubei Biocause Heilen Pharmaceutical Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Minjie","middleName":"","lastName":"Liao","suffix":""},{"id":458185905,"identity":"bf8782c5-5ff5-483b-86ea-083d78b8f0f3","order_by":5,"name":"Min Kan","email":"","orcid":"","institution":"Nanjing Healthnice Pharmaceuticals Technology Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Kan","suffix":""},{"id":458185906,"identity":"e95e9b2a-2171-4fc2-8940-1f8ea6b53e53","order_by":6,"name":"Juxiang Zhuang","email":"","orcid":"","institution":"Nanjing Healthnice Pharmaceuticals Technology Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Juxiang","middleName":"","lastName":"Zhuang","suffix":""},{"id":458185907,"identity":"ce5181ce-4738-4e7e-b136-ca35a714f595","order_by":7,"name":"Angeng Wang","email":"","orcid":"","institution":"Hefei Hospital Affiliated to Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Angeng","middleName":"","lastName":"Wang","suffix":""},{"id":458185908,"identity":"aeedb3b4-d8c3-4e08-b752-434fe21d21bb","order_by":8,"name":"Xiangyun Meng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAu0lEQVRIiWNgGAWjYBACA+YDDAyM/yTk2NjbDxCphS0BSLLZGPPxnEkgSUta4jwJBwPitJizcadJ8/AcTm+TYEhg+FGxjbAWyzbezcY8Eodz26QbDzD2nLlNhMPu9258zGMA1CJzIIGZsY0YLcd4NxzmSTicziaRYEC0FqAtB9ISSNKy2XBug41hGzCQDxLnl2O82yTeNkjIy7e3H3zwo4IILSDAxANlHCBOPRAw/iBa6SgYBaNgFIxIAAAq7Ts4H5uEmgAAAABJRU5ErkJggg==","orcid":"","institution":"Hefei Hospital Affiliated to Anhui Medical University","correspondingAuthor":true,"prefix":"","firstName":"Xiangyun","middleName":"","lastName":"Meng","suffix":""}],"badges":[],"createdAt":"2025-04-21 03:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6492168/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6492168/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s40360-025-01001-2","type":"published","date":"2025-10-06T15:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83213400,"identity":"7ff5e863-d17f-433b-9c24-b03abed042d4","added_by":"auto","created_at":"2025-05-21 08:45:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180164,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design and flowchart. Abbreviations: T, test drug; R, reference drug; n, number of subjects.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6492168/v1/b5a8e309a7a51cde212d4083.jpg"},{"id":83211726,"identity":"d656d4e4-9d14-4f75-ab0d-ee6825bc2e52","added_by":"auto","created_at":"2025-05-21 08:37:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":64068,"visible":true,"origin":"","legend":"\u003cp\u003eFebuxostat concentration-time curves in healthy volunteers after oral administration of the test formulation and the reference formulation on fasting (mean ± SD, n\u003cem\u003e \u003c/em\u003e= 39). (A) Linear scale; (B) logarithmic scale. SD, standard deviation.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6492168/v1/6b97b19752ec5f4e503a5ebf.jpg"},{"id":83213402,"identity":"7a76c65f-6ec3-4407-878a-a557afc2bb31","added_by":"auto","created_at":"2025-05-21 08:45:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":63220,"visible":true,"origin":"","legend":"\u003cp\u003eFebuxostat concentration-time curves in healthy volunteers after oral administration of the test formulation and the reference formulation on fed (mean ± SD, n = 40). (A) Linear scale; (B) logarithmic scale. SD, standard deviation.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6492168/v1/0a09b7c3f32835b32e3f603d.jpg"},{"id":93419669,"identity":"08ac57f2-9182-439d-b4d5-05eb596b7f20","added_by":"auto","created_at":"2025-10-13 16:05:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1266970,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6492168/v1/70c7b496-eb7a-406a-91fd-808fb8f416e1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bioequivalence Evaluation of Generic Febuxostat versus Feburic ® in Healthy Chinese Subjects: A Randomized Crossover Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eXanthine oxidase inhibitors, represented by allopurinol and febuxostat, constitute the primary pharmacological approach for reducing uric acid production. Although allopurinol has been widely used since the 1960s, its potential for severe adverse reactions, including Stevens-Johnson syndrome, limits its use in patients with renal impairment [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. In contrast, febuxostat, as a novel non-purine selective inhibitor targeting both oxidized and reduced forms of xanthine oxidase, offers comparable urate-lowering efficacy with superior safety, especially for patients with mild-to-moderate renal dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Following its initial development in Japan (2004), febuxostat received successive approvals from the EMA (2008), FDA (2009), and the China National Food and Drug Administration (CFDA) (2013) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In China, the recommended daily doses are 40 mg or 80 mg, with the brand-name product Feburic\u0026reg; (Teijin Pharma Limited) available as 20 mg and 40 mg tablets [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe development of generic febuxostat formulations meets a critical need for affordable urate-lowering therapies. Bioequivalence studies serve as the regulatory standard for demonstrating therapeutic equivalence, comparing key pharmacokinetic (PK) parameters including maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e), an indicator of absorption rate, and area under the plasma concentration-time curve (AUC), which reflects absorption extent. Regulatory approval requires that the 90% confidence intervals (CIs) for geometric mean ratios (GMRs) of these parameters fall within the 80\u0026ndash;125% equivalence range [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In this context, our test formulation represents a cost-effective alternative to the reference product Feburic\u0026reg; (Teijin Pharma Limited). As a bioequivalent agent approved by regulatory authorities, it provides comparable PK performance while enhancing treatment accessibility for gout patients in China.\u003c/p\u003e \u003cp\u003eExisting PK studies have documented febuxostat disposition in various populations, including Chinese subjects [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. While comparative analyses demonstrate ethnic variations between Chinese and Caucasian populations [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and a single-dose study showed comparable fasting-state profiles in Chinese males [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], critical knowledge gaps persist regarding food effects and gender differences in Chinese individuals [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Population PK (PopPK) modeling reveals food reduces febuxostat bioavailability by 67% in this population [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], with multi-peak absorption patterns observed across ethnic groups [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. To address these evidence gaps, we conducted a randomized, single-dose, open-label, two-sequence crossover study comparing a 40 mg test formulation (Hubei Biocause Heilen Pharmaceutical) with Feburic\u0026reg; in healthy Chinese volunteers of both sexes under fasting and fed conditions. This dual-state design enables comprehensive characterization of both the fasted and fed PK profiles while accounting for the established food effects and absorption variability in the target population.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Materials\u003c/h2\u003e \u003cp\u003eThe test formulation (T) of febuxostat tablets (40 mg; batch no. 20230803) was produced and provided by Hubei Biocause Heilen Pharmaceutical Co., Ltd. Reference product (R, Feburic\u0026reg;; 40 mg; batch no. 4221B) was sourced from original manufacturer (Teijin Pharma Limited, Japan), ensuring traceability. Analytical standards included febuxostat reference substance (99.4% purity; batch no. 4326-005A1) and the internal standard febuxostat-d7 (97.9% purity; batch no. 4296-093A3), both obtained from TLC Pharmaceutical Standards. All solvents were HPLC grade, including ultrapure water, acetonitrile, methanol, formic acid, and ammonium acetate.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSubjects\u003c/h3\u003e\n\u003cp\u003e Healthy Chinese volunteers who met all inclusion criteria were enrolled in this study after providing written informed consent. Eligible participants included males and females aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years with body mass index (BMI) between 19.0 and 26.0 kg/m\u003csup\u003e2\u003c/sup\u003e (inclusive), with minimum body weights of 50.0 kg for males and 45.0 kg for females. All subjects demonstrated normal or clinically insignificant results in physical examinations (including vital signs), electrocardiograms, chest X-rays, and laboratory tests (hematology, biochemistry, and urinalysis). Female participants of childbearing potential agreed to use effective contraception from 30 days before consent until 90 days after the final study drug administration and had no immediate pregnancy plans.\u003c/p\u003e \u003cp\u003eExclusion criteria included: serum uric acid levels\u0026thinsp;\u0026ge;\u0026thinsp;1.2 times the upper limit of normal; history of significant chronic illness or allergic conditions; recent use of medications or health supplements (within 14 days) or planned vaccinations (within 28 days post-study); major surgery within the past year or planned during the study; participation in other clinical trials within 90 days; smoking\u0026thinsp;\u0026ge;\u0026thinsp;5 cigarettes/day or inability to abstain during the study; alcohol consumption\u0026thinsp;\u0026gt;\u0026thinsp;14 units/week or positive alcohol breath test; and current pregnancy or breastfeeding status.\u003c/p\u003e\n\u003ch3\u003eStudy Design, Ethics, and Randomization\u003c/h3\u003e\n\u003cp\u003eThis randomized, open-label, single-dose, two-sequence, two-period crossover study was conducted at the Phase I Clinical Trial Center of Hefei Hospital Affiliated to Anhui Medical University (The Second People\u0026rsquo;s Hospital of Hefei). The study protocol was approved by the Clinical Trial Ethics Committee of The Second People\u0026rsquo;s Hospital of Hefei (Approval No. 2023 Ethical Opinion-Medical-037-01) and registered (CTR20233483) at the Chinese Clinical Trial Registration Platform (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.chinadrugtrials.org.cn/index.html\u003c/span\u003e\u003cspan address=\"http://www.chinadrugtrials.org.cn/index.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), complying with the Declaration of Helsinki [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], ICH-GCP guidelines [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and China National Medical Products Administration (NMPA) regulations. The execution dates of the study were from November 28, 2023, to December 26, 2023.\u003c/p\u003e \u003cp\u003eSample size determination was based on China NMPA data showing intra-individual variability for febuxostat tablets (C\u003csub\u003emax\u003c/sub\u003e: 7.29\u0026ndash;37.02%; AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e: 5.86\u0026ndash;20.49%; AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e: 5.93\u0026ndash;7.83%). Using PASS 11.0 software with α\u0026thinsp;=\u0026thinsp;0.05, power\u0026thinsp;=\u0026thinsp;80%, and GMR\u0026thinsp;=\u0026thinsp;0.95, we calculated that 31 evaluable subjects per group would provide adequate statistical power. Accounting for potential 20% dropout, we enrolled 40 subjects per group (80 total). Randomization employed a block design (size\u0026thinsp;=\u0026thinsp;4) generated using SAS\u0026reg; 9.4 (PROC PLAN; fixed seed\u0026thinsp;=\u0026thinsp;517393506), with subjects allocated to either TR (test\u0026rarr;reference) or RT (reference\u0026rarr;test) sequences and a 7-day washout between periods. While the study was open-label, bioanalysts remained blinded to treatment sequences during PK analysis.\u003c/p\u003e \u003cp\u003eIn the fasting condition, participants fasted\u0026thinsp;\u0026ge;\u0026thinsp;10 h before receiving a single 40 mg dose with 240 mL water. For the fed condition, subjects consumed a standardized high-fat meal (800\u0026ndash;1000 kcal; 50% fat, 15% protein, 25% carbohydrates) 30 minutes before dosing. Water intake was restricted 1 h pre- and post-dose, with standardized meals provided at 4 h and 10 h post-dose. All protocol deviations were documented and reported to the Ethics Committee.\u003c/p\u003e\n\u003ch3\u003eBlood Sampling and Processing\u003c/h3\u003e\n\u003cp\u003ePK blood samples (4 mL each) were collected in K\u003csub\u003e2\u003c/sub\u003e-EDTA anticoagulant tubes (Jiangsu YuLi Medical Instrument Co., Ltd) in each stage (pre-dose and at 10 min, 20 min, 40 min, 1 h, 1 h 20 min, 1 h 40 min, 2 h, 2 h 20 min, 2 h 40 min, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 36 h after administration under fasting condition; pre-administration and at 10 min, 20 min, 40 min, 1 h, 1 h 20 min, 1 h 40 min, 2 h, 2 h 20 min, 2 h 40 min, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 24 h, 36 h after administration under fed condition). The plasma samples were centrifuged (2000 g, 10 min, 4\u0026deg;C) within 60 min, and the plasma separated was stored at -80\u0026deg;C until PK analysis.\u003c/p\u003e\n\u003ch3\u003ePK analysis\u003c/h3\u003e\n\u003cp\u003eA validated, specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was employed to analyze the plasma concentration of febuxostat in human. Waters Acquity (Waters Corporation, Milford, Massachusetts) and Sciex API 6500 Triple Quad mass spectrometer Applied Biosystem with an electrospray ionization source were combined for the LC-MS/MS analysis.\u003c/p\u003e \u003cp\u003eExionLC and Sciex ExionLC API 6500\u003csup\u003e+\u003c/sup\u003e Triple Quad mass spectrometer Applied Biosystem (Applied Biosystems/Sciex, USA) with an electrospray ionization source were combined for the LC-MS/MS analysis. Febuxostat-d7 was used as an internal standard. The linear range is 5.00\u0026thinsp;~\u0026thinsp;5000 ng/mL for febuxostat. The lower limit of quantification was 5.00 ng/mL. The maximum precision (CV%) of the quality control sample was 3.5%. The accuracy bias (%) from the theoretical concentration of the quality control samples was between 1.2% and 5.7%. The analytes in the plasma maintained their stability after storage at room temperature for 28 h. Similarly, the analytes in the treated plasma samples remained stable even after storage at 4℃ for 237 h and in an automatic sampler for 196 h. Furthermore, the analytes in plasma remain stable even after being stored at -20℃ and \u0026minus;\u0026thinsp;80℃ for 13 days and 49 days, respectively. The plasma samples were placed at -20℃ and \u0026minus;\u0026thinsp;80℃ for five freeze-thaw cycles remained stable.\u003c/p\u003e \u003cp\u003eChromatographic separation employed an ACE Excel 3 SuperC\u003csub\u003e18\u003c/sub\u003e column (50 mm\u0026times;2.1 mm, 3 \u0026micro;m). The mobile phases A (10 mM ammonium acetate containing 0.1% formic acid) and B (acetonitrile) were eluted using a gradient, with a flow rate of 0.3 mL/min, a starting ratio of 45% for pump B, an injection volume of 2.0 \u0026micro; L, and the column temperature was set to 40℃.\u003c/p\u003e \u003cp\u003eQuantitative analysis of febuxostat and its internal standard (febuxostat-d7) was performed using electrospray ionization (ESI) in positive ion mode. The mass spectrometer was operated with the following optimized parameters: ion spray voltage of +\u0026thinsp;5500 V, source temperature of 500℃, collision gas (N2) pressure of High, spray gas (N2) pressure of 55 psi, air curtain gas (N2) pressure of 25 psi, and entrance potential of 10 V. Quantitation was performed by monitoring the transitions at m/z 317.3\u0026rarr;m/z 261.1 for febuxostat and m/z 324.2\u0026rarr;m/z 262.1 for febuxostat-d7. The dwell time was set to 150 ms. Ionization mode was electric spray ionization source and positive ion condition scanning, and scanning mode was multi reaction ion monitoring mode.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSafety Analysis\u003c/h2\u003e \u003cp\u003eThe safety of febuxostat tablet was evaluated based on observation of adverse events (AEs), vital signs (temperature, blood pressure, and pulse), laboratory tests (hematology, biochemistry, urinalysis, coagulation function, and blood pregnancy), physical examination, and electrocardiography. Vital signs were monitored in each stage (pre-administration and at 2 h, 6 h, 12 h, 24 h, and 36 h after administration for both fasting group and fed group). Other examinations were conducted at screening and early exit or removal from the study. AEs were monitored throughout the study and all recorded AEs were graded according to the National Cancer Institute Common Terminology Criteria for AEs (CTCAE 5.0 graded). All AEs were followed up until elimination or stabilization of the events.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003ePK and Statistical Analysis\u003c/h3\u003e\n\u003cp\u003ePK parameters were calculated using non-compartmental analysis with Phoenix WinNonlin software (version 8.0, Certara Inc., Princeton, NJ, USA). Analysis of variance (ANOVA) was performed for significance test. In the analysis of variance model, the administration order, formulation, and period were used as fixed effects, while the subjects (order) are used as random effects. The statistical significance of differences between administration sequences, formulations, and cycles was analyzed by SAS 9.4 (SAS Institute Inc., Cary, NC, USA), with a significance level of α\u0026thinsp;=\u0026thinsp;0.05. The major PK parameters included C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, and AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e. The secondary PK parameters included the time of the maximum plasma concentration (T\u003csub\u003emax\u003c/sub\u003e) and terminal half-life (\u003cem\u003et\u003c/em\u003e\u003csub\u003e1/2\u003c/sub\u003e) of febuxostat in plasma were also measured. These parameters were described as mean value (mean) and standard deviation (SD). After performing natural logarithmic transformation on PK parameters using a bioequivalence dataset, variance analysis was first performed, and then bioequivalence evaluation was performed using CI method. After a natural logarithmic conversion, the 90% CIs of GMRs (T/R) were calculated. The two formulations was considered to bioequivalent if 90% CIs fell within 80.00%-125.00% for AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, AUC\u003csub\u003e0\u0026minus; \u0026infin;\u003c/sub\u003e, and C\u003csub\u003emax\u003c/sub\u003e. AEs that occurred in this study will be statistically described based on incidence, severity, and correlation analysis between AEs and the study drug.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eSubject characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 153 volunteers were screened, with 80 Han Chinese subjects enrolled (40 in each fasting and fed group). Demographic characteristics were comparable between groups (Table\u0026nbsp;1), including age, height, weight, and BMI (\u003cem\u003eP\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u0026gt;0.05). In the fasting group, 40 participants (36 males, 4 females) were randomized, with 38 completing the study. One subject withdrew before the first cycle, and the other only completed the first cycle. In the fed group, all 40 participants (38 males, 2 females) randomized and successfully completed the trial. The study design is summarized in Fig. 1. Overall, 79 subjects were included in the PK concentration set, PK parameter set, bioequivalence analysis set, safety analysis set, and full analysis set.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e\u0026nbsp; Demographic Characteristics of participants in the Fasting and Fed Studies\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"764\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 88px;\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 339px;\"\u003e\n \u003cp\u003eFasting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 321px;\"\u003e\n \u003cp\u003eFed\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eSequence A (R-T) (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eSequence B (T-R) (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(n=40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eSequence A (R-T) (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eSequence B (T-R) (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(n=40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge(years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e0.966\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e0.494\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e27.55\u0026plusmn;6.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e27.65\u0026plusmn;7.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e27.60\u0026plusmn;7.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e29.15\u0026plusmn;5.96\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e30.60\u0026plusmn;7.26\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e29.88\u0026plusmn;6.60\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e28.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e28.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e28.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e31.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e29.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e30.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e18.0, 48.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e19.0, 47.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e18.0, 48.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e19.0, 40.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e19.0, 45.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e19.0, 45.0\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight(cm)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e0.897\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e167.23\u0026plusmn;5.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e169.33\u0026plusmn;5.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e168.28\u0026plusmn;5.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e170.45\u0026plusmn;4.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e170.18\u0026plusmn;8.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e170.31\u0026plusmn;6.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e166.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e170.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e168.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e170.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e170.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e170.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e155.5, 180.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e159.0, 177.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e155.50, 180.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e160.50, 179.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e149.0, 180.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e149.0, 180.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight(kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e0.127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e0.228\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e62.82\u0026plusmn;6.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e66.45\u0026plusmn;7.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e64.63\u0026plusmn;7.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e65.48\u0026plusmn;6.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e68.51\u0026plusmn;8.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e66.99\u0026plusmn;7.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMedian\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e62.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e67.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e64.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e64.95\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e70.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e66.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003eMin, Max\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e52.10, 76.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e50.20,76.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e50.20, 76.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e55.10, 79.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e53.60, 80.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e53.60, 80.10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI(kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e0.238\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e22.43\u0026plusmn;1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e23.12\u0026plusmn;1.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e22.43\u0026plusmn;1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e22.53\u0026plusmn;2.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e23.61\u0026plusmn;2.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e23.07\u0026plusmn;2.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e22.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e23.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e22.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e22.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e24.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e23.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e19.60, 25.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e19.90, 25.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 99px;\"\u003e\n \u003cp\u003e19.60, 25.90\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 53px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e19.20, 25.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e19.50, 26.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e19.20, 26.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e BMI, body mass index; R, reference drug; \u0026nbsp;T, test drug.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePK results and bioequivalence evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood samples from all 79 subjects were analyzed. Linear and semi-logarithmic mean plasma drug concentration-time curves of febuxostat after single-dose administration of T and R formulations are shown in Fig.\u0026nbsp;2A/B (fasting) and Fig.\u0026nbsp;3A/B (fed). The curves for T and R overlapped closely under both conditions.\u0026nbsp;Major PK parameters\u0026nbsp;(Table\u0026nbsp;2)\u0026nbsp;revealed comparable mean values for\u0026nbsp;C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0-t\u003c/sub\u003e, and AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e between T and R, indicating similar PK profiles. Bioequivalence was confirmed, as all 90% CIs for GMRs fell within the 80.00-125.00% range (Table 3). No significant difference in T\u003csub\u003emax\u003c/sub\u003e were observed (\u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026gt;0.05),\u0026nbsp;supporting\u0026nbsp;consistent\u0026nbsp;absorption rates and extents.\u0026nbsp;Notably, C\u003csub\u003emax\u003c/sub\u003e values differed significantly between fasting and fed states, with postprandial values markedly lower than fasting values.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePharmacokinetic Parameters of Febuxostat (Test vs. Reference) under fasting and fed conditions\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"745\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 134px;\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 295px;\"\u003e\n \u003cp\u003eFasting condition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 301px;\"\u003e\n \u003cp\u003eFed condition\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003eTest (n=38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003eReference (n=39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003eTest (n=38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003eReference (n=39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003eT\u003csub\u003emax\u0026nbsp;\u003c/sub\u003e(h)\u003csup\u003e■\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e1 (0.33, 4.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e1 (0.33, 4.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003e1.67 (0.67, 4.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e1.5 (0.67, 5.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003eC\u003csub\u003emax\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e2097.95\u0026plusmn;639.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e2067.513\u0026plusmn;723.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003e1353.050\u0026plusmn;387.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e1400.225\u0026plusmn;486.14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0-t\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e\u0026middot;h)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e6011.93\u0026plusmn;1918.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e5818.290\u0026plusmn;1851.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003e5285.485\u0026plusmn;1321.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e5078.916\u0026plusmn;1198.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0-\u0026infin;\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e\u0026middot;h)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e6120.16\u0026plusmn;1930.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e5940.61\u0026plusmn;1845.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003e5364.85\u0026plusmn;1329.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e5164.07\u0026plusmn;1216.21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u0026lambda;\u003csub\u003ez\u0026nbsp;\u003c/sub\u003e(h\u003csup\u003e-1\u003c/sup\u003e)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e0.111\u0026plusmn;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e0.114\u0026plusmn;0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003e0.144\u0026plusmn;0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e0.149\u0026plusmn;0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cem\u003et\u003c/em\u003e\u003csub\u003e1/2\u0026nbsp;\u003c/sub\u003e(h)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 155px;\"\u003e\n \u003cp\u003e6.463\u0026plusmn;1.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 140px;\"\u003e\n \u003cp\u003e6.448\u0026plusmn;1.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 147px;\"\u003e\n \u003cp\u003e5.036\u0026plusmn;1.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 154px;\"\u003e\n \u003cp\u003e4.978\u0026plusmn;1.28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNotes\u003c/strong\u003e: \u003csup\u003e■\u003c/sup\u003eValues were presented as median (min, max); *Values were presented as mean \u0026plusmn; SD (%CV).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e AUC\u003csub\u003e0-t,\u003c/sub\u003e area under the plasma concentration-time curve from time zero to the last measurable concentration;AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e, area under the plasma concentration-time curve from time zero to infinity; \u0026nbsp;C\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration;T\u003csub\u003emax\u003c/sub\u003e, time to reach maximum plasma concentration;\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u0026lambda;\u003csub\u003ez\u0026nbsp;\u003c/sub\u003e,Terminal elimination rate constant; \u003cem\u003et\u003c/em\u003e\u003csub\u003e1/2\u003c/sub\u003e, elimination half-life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e3\u0026nbsp;\u003c/strong\u003eBioequivalence statistics for pharmacokinetic parameters\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"775\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 129px;\"\u003e\n \u003cp\u003eParameter\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 202px;\"\u003e\n \u003cp\u003eGeometric mean and ratio\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003eCV (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 101px;\"\u003e\n \u003cp\u003e90%CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 56px;\"\u003e\n \u003cp\u003ePower (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 226px;\"\u003e\n \u003cp\u003eANOVA \u003cem\u003ep\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003evalue\u003csup\u003e#\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003eTest\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e(T/R)%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eSequence\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003ePeriod\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003eFormulations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" style=\"width: 775px;\"\u003e\n \u003cp\u003eFasting\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eC\u003csub\u003emax\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e1986.811\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e1946.915\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e102.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e24.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e92.87-112.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e96.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0.387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.371\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.718\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0-t\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e\u0026middot;h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e5614.802\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5523.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e101.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e6.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e99.08-104.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026gt;99.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.889\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.288\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0-\u0026infin;\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e\u0026middot;h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e5723.110\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5652.396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e101.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e6.52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e98.73-103.84\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026gt;99.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0123\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.411\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"10\" style=\"width: 775px;\"\u003e\n \u003cp\u003eFed\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eC\u003csub\u003emax\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e1301.433\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e1325.698\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e98.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e18.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e91.72-105.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e99.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0.076\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.337\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.649\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0-t\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e\u0026middot;h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e5123.248\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e4942.635\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e103.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e6.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e101.16-106.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026gt;99.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0.079\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 129px;\"\u003e\n \u003cp\u003eAUC\u003csub\u003e0-\u0026infin;\u0026nbsp;\u003c/sub\u003e(ng\u0026middot;mL\u003csup\u003e-1\u003c/sup\u003e\u0026middot;h)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 72px;\"\u003e\n \u003cp\u003e5203.560\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 74px;\"\u003e\n \u003cp\u003e5027.266\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e103.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e6.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 101px;\"\u003e\n \u003cp\u003e101.13-105.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 56px;\"\u003e\n \u003cp\u003e\u0026gt;99.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94px;\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNotes\u003c/strong\u003e: \u003csup\u003e#\u003c/sup\u003eANOVA was performed on log-transformed parameters (lnAUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e, lnAUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e,\u0026nbsp;lnC\u003csub\u003emax\u003c/sub\u003e); \u003cem\u003eP\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u0026lt;\u0026nbsp;\u003c/em\u003e0.05 indicates statistical significance.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e AUC\u003csub\u003e0-t,\u003c/sub\u003e area under the plasma concentration-time curve from time zero to the last measurable concentration;AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e, area under the plasma concentration-time curve from time zero to infinity; CI, confidence interval; C\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration; CV, coefficient of variation; R, reference drug;\u0026nbsp;T, test drug.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety results\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the fasting group, a total of 6 AEs were reported among 5 subjects in the fasting group, yielding an AE incidence rate of 12.8% (5/39 subjects). Among these, 5 AEs in 4 subjects were assessed as \u0026quot;likely related\u0026quot; to the study drug, while 1 AE in 1 subject was deemed \u0026quot;possibly related\u0026quot;, collectively classified as adverse drug reactions (ADRs) with an ADR incidence rate of 12.8%. All AEs were Grade 1 (mild) in severity, and no serious adverse events (SAEs) occurred (Table\u0026nbsp;4).\u003c/p\u003e\n\u003cp\u003eIn the fed group, 13 AEs were reported among 10 subjects, corresponding to an AE incidence rate of 25.0% (10/40 subjects). Of these, 13 AEs (in 10 subjects) were categorized as \u0026quot;possibly related\u0026quot; or \u0026quot;very likely related\u0026quot; to the investigational drug, resulting in an ADR incidence rate of 25.0%. One AE was Grade 2 (moderate), while the remainder were Grade 1; no SAEs were observed (Table\u0026nbsp;4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4\u0026nbsp;\u003c/strong\u003eSummary of adverse events\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"132%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 44px;\"\u003e\n \u003cp\u003eFasting\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" style=\"width: 44px;\"\u003e\n \u003cp\u003eFed\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003eTest\u0026nbsp;(n=38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003eReference\u0026nbsp;(n=39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 9px;\"\u003e\n \u003cp\u003eTotal, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003eTest\u0026nbsp;(n=40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 17px;\"\u003e\n \u003cp\u003eReference\u0026nbsp;(n=40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 8px;\"\u003e\n \u003cp\u003eTotal, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eInstance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eInstance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eInstance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003eInstance\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003en (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eTotal AEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e3(7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2(5.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5(12.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6(12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e7(12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e10(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eAEs of grade 1 and above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e3(7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e2(5.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e5(12.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e6(12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e6(12.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e10(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eAEs of grade 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1(2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e1(2.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eAEs of grade 3 and above\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eSAEs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003eAEs leading to exit\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eNotes\u003c/strong\u003e: n (%) is the proportion of adverse drug reactions among all subjects taking febuxostat.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations\u003c/strong\u003e: AEs, adverse events; SAE, serious adverse event; n, number of subjects;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo subjects withdrew from the trial due to AEs, and all reported AEs resolved with recovery or remission. There were no unexpected AEs or ADRs. These findings demonstrate that both T and R formulations of febuxostat (40 mg) were well-tolerated and exhibited a favorable safety profile in healthy Chinese subjects under fasting and fed conditions.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSince its FDA approval in 2009, febuxostat has demonstrated equivalent efficacy and tolerability in long-term management of hyperuricemia in gout patients, prompting significant interest in generic development [7].\u0026nbsp;The bioequivalence of the generic febuxostat supports its use as a cost-effective alternative, potentially improving medication access in resource-limited settings. The recommended initial dosage for oral administration of febuxostat tablets is 40 mg once daily, with potential escalation to 80 mg if serum uric acid remains \u0026gt;6 mg/dL (\u0026asymp;360 \u0026mu;mol/L) after two weeks\u0026nbsp;[16].\u003csup\u003e\u0026nbsp;\u003c/sup\u003eGeneric formulations offer substantial cost savings while maintaining therapeutic equivalence when bioequivalence is established.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs a standard bioequivalence test, healthy male and female volunteers were commonly given preference, which could reduce the impact of individual and gender differences. In accordance with FDA guidelines for Feburic\u003csup\u003e\u0026reg;\u003c/sup\u003e, the bioequivalence of the T and R should be evaluated under the fasting and fed states, respectively. There are indeed few bioequivalence studies on single dose administration of 40 mg febuxostat tablet by females. The published PK properties and bioequivalent results of febuxostat might be unsuitable for Chinese female volunteers under both fasting and fed states [7,\u0026nbsp;17,\u0026nbsp;18].\u0026nbsp;This randomized, single-dose, open-label, two-sequence crossover trial evaluated PK\u0026nbsp;characteristics and bioequivalence of T versus R\u0026nbsp;febuxostat (40 mg) in healthy Chinese volunteers under fasting and fed conditions. Notably, our study included both sexes, addressing a gap in existing literature where most bioequivalence data derive from male subjects.\u0026nbsp;Study design followed FDA\u0026nbsp;[19]\u0026nbsp;and NMPA guidelines, with Teijin Pharma\u0026apos;s Feburic\u003csup\u003e\u0026reg;\u003c/sup\u003e selected as R based on NMPA\u0026apos;s reference preparation standards.\u003c/p\u003e\n\u003cp\u003eMethodologically, in accordance with FDA guidance on\u0026nbsp;\u0026ldquo;Bioequivalence (BE) Studies with PK Endpoints for Drugs Submitted Under an ANDA\u0026rdquo; [20],\u003csup\u003e\u0026nbsp;\u003c/sup\u003ewe quantified febuxostat plasma concentrations (rather than metabolites) using a validated LC-MS/MS method\u0026nbsp;[21, 22].\u0026nbsp;Demographic characteristics demonstrated no significant intergroup differences. Bioequivalence was established, with 90%\u0026nbsp;CIs for\u0026nbsp;GMRs of C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0-t\u003c/sub\u003e, and AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e falling within the 80-125% acceptance range under both fasting and fed conditions. Comparative analysis of T\u003csub\u003emax\u003c/sub\u003e showed no statistically significant formulation differences (\u003cem\u003eP\u003c/em\u003e \u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003eOur fasting-state PK parameters were consistent with previous reports [23],\u003csup\u003e\u0026nbsp;\u003c/sup\u003ealthough observed AUC values were moderately elevated\u0026mdash;a difference potentially explained by the inclusion of female participants (35 males:4 females) in our cohort. This finding corroborates established evidence of gender-related PK variations, wherein female subjects typically demonstrate higher C\u003csub\u003emax\u003c/sub\u003e and AUC values, likely attributable to body weight differences [8]. Interestingly, our values exceeded those reported in Caucasian populations [17,\u0026nbsp;24], corroborating reports of higher febuxostat exposure in Asians versus Caucasians, independent of body weight [17].\u003csup\u003e\u0026nbsp;\u003c/sup\u003eThese ethnic PK variations underscore the importance of population-specific dosing considerations. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFollowing oral administration of a single 40 mg dose, both T and R formulations demonstrated rapid absorption under fasting conditions, with median T\u003csub\u003emax\u003c/sub\u003e values of 1 h (range: 0.33-4.50 h) and 1 h (range: 0.33-4.51 h), respectively. Consistent with population PK models demonstrating 67% reduced bioavailability under fed conditions [11].\u003csup\u003e\u0026nbsp;\u003c/sup\u003ePrevious studies have established that food effects primarily manifest as alterations in absorption rate and extent for orally administered medications [25]. Specifically, a PopPK study of febuxostat in healthy Chinese subjects demonstrated that concomitant high-fat meal consumption decreased both the absorption rate and bioavailability of febuxostat [10], which aligns precisely with our observations.\u003c/p\u003e\n\u003cp\u003eIn our fed cohort, absorption was moderately delayed compared to fasting conditions, with median T\u003csub\u003emax\u003c/sub\u003e values of 1.67 h (range: 0.67-4.5 h) and 1.5 h (range: 0.67-5 h) for T and R formulations, respectively. The observed reductions in systemic exposure under fed conditions\u0026mdash;approximately 35% for C\u003csub\u003emax\u003c/sub\u003e, 12% for AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e, and 23% for \u003cem\u003et\u003c/em\u003e\u003csub\u003e1/2\u003c/sub\u003e\u0026mdash;were consistent with the food effects described in Feburic\u003csup\u003e\u0026reg;\u003c/sup\u003e prescribing information. Importantly, the effects of high-fat diet on both formulations showed comparable patterns, with 90% CIs for GMRs of all primary PK parameters (AUC\u003csub\u003e0-t\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, and AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e) falling within the 80-125% bioequivalence range. These results demonstrate that the generic formulation maintains similar absorption and elimination characteristics to the reference product regardless of prandial state, supporting its administration without strict meal timing requirements [26].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe safety profiles of the T and R formulations were comparable. Both formulations were well tolerated, with no SAEs observed. According to previous studies and the prescribing information for the reference drug, the most common AEs were mild and transient, including liver dysfunction, nausea, joint pain, rash, and dizziness (incidence \u0026gt;1%) [27,\u0026nbsp;28].\u0026nbsp;In our study, two subjects experienced\u0026nbsp;ADRs of liver dysfunction (one each in fasting and fed groups), and one subject reported dizziness in the fasting group. Other common\u0026nbsp;AEs described in the literature were not observed in our study, which may be related to the single-dose administration. Nevertheless, clinicians should remain vigilant for these potential AEs during febuxostat therapy.\u003c/p\u003e\n\u003cp\u003eThree limitations warrant consideration: the single-dose design in healthy volunteers may not reflect chronic use patterns, the small female cohort (n=6) limits gender-specific conclusions, and the absence of patient populations requires confirmation of clinical outcomes. Further studies in gout patients and special populations (particularly renal impairment) are essential to fully establish therapeutic equivalence. These results nevertheless provide robust PK evidence supporting the generic\u0026apos;s use while identifying key areas for future research.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study provides robust pharmacokinetic evidence supporting the clinical application of a generic febuxostat formulation, demonstrating bioequivalence to the reference product (Feburic\u003csup\u003e\u0026reg;\u003c/sup\u003e) under both fasting and fed conditions in healthy Chinese subjects. The validated LC-MS/MS analytical method and randomized crossover design ensured reliable assessment of key pharmacokinetic parameters, all of which met regulatory bioequivalence criteria. These findings support the generic formulation as a therapeutically equivalent and cost-effective alternative for gout management, while highlighting the importance of considering food effects in clinical dosing regimens.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADR, adverse drug reaction; AE, adverse event; AUC, area under the curve; AUC\u003csub\u003e0-t,\u003c/sub\u003e area under the plasma concentration-time curve from time zero to the last measurable concentration;AUC\u003csub\u003e0-\u0026infin;\u003c/sub\u003e, area under the plasma concentration-time curve from time zero to infinity; BMI, body mass index; CI, confidence interval; C\u003csub\u003emax\u003c/sub\u003e, maximum plasma concentration; CV, coefficient of variation; FDA, US Food and Drug Administration; GCP, Good Clinical Practice; GMR, geometric mean ratio; HPLC, high performance liquid chromatography; ICH, International Council for Harmonisation; LC-MS/MS, liquid chromatography-tandem mass spectrometry; NMPA, National Medical Products Administration; PK, pharmacokinetic; PopPK, population pharmacokinetic; \u0026nbsp;R, reference drug;\u0026nbsp;SAE, serious adverse event;\u0026nbsp;T, test drug;\u0026nbsp;T\u003csub\u003emax\u003c/sub\u003e, time to reach maximum plasma concentration;\u0026nbsp;t\u003csub\u003e1/2\u003c/sub\u003e, elimination half-life.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study passed the review of Clinical Trial Ethics Committee of The Second People\u0026rsquo;s Hospital of Hefei (Approval No. 2023 Ethical Opinion-Medical-037-01) . The written informed consents was obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOriginal data supporting the Conclusions of this study will be provided by the author (Fengling Wang) and should be retained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe author(s) report no conflicts of interest in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Hubei Biocause Heilen Pharmaceutical Co., Ltd. The funder was not involved in the study design, data collection, analysis, interpretation, article writing, or the decision to submit the manuscript for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was designed by XYM and FLW. FLW, XY, FL and AGW performed the research. FLW. FLW, XY and FL wrote the paper. HLK, MJL, MK and JXZ participated in the acquisition of data and statistics. The author (s) gave final approval of the version to be published and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all enrolled participants, investigators, and individuals who contributed to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026apos; information (optional)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003ePhase I Clinical Trial Center, Hefei Hospital Affiliated to Anhui Medical University (The Second People\u0026rsquo;s Hospital of Hefei), Hefei 230011, Anhui Province, China.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eErnst ME, Fravel MA. Febuxostat: a selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout. Clin Ther. 2009;31(11):2503\u0026ndash;2518. doi:10.1016/j.clinthera.2009.11.033\u003c/li\u003e\n\u003cli\u003eBecker MA, Schumacher HR, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450\u0026ndash;2461. doi:10.1056/NEJMoa050373\u003c/li\u003e\n\u003cli\u003eZhou Q, Su J, Zhou T, et al. A study comparing the safety and efficacy of febuxostat, allopurinol, and benzbromarone in Chinese gout patients: a retrospective cohort study. Int J Clin Pharmacol Ther. 2017;55(2):163\u0026ndash;168. doi:10.5414/CP202629\u003c/li\u003e\n\u003cli\u003eHowland RH. Evaluating the bioavailability and bioequivalence of generic medications. J Psychosoc Nurs Ment Health Serv. 2010;48(1):13\u0026ndash;16. doi:10.3928/02793695-20091204-07\u003c/li\u003e\n\u003cli\u003eBhushan R, Martens J. Generic pharmaceuticals, regulatory aspects, bioequivalence investigation, and perception. Expert Opin Drug Saf. 2024;23(2):177\u0026ndash;186. doi:10.1080/14740338.2024.2305709\u003c/li\u003e\n\u003cli\u003eUS Food and Drug Administration. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Center for Drug Evaluation and Research (CDER); 2001. https://www.fda.gov/media/70858/download. Accessed 24 Jan, 2025.\u003c/li\u003e\n\u003cli\u003eLuo Z, Nan F, Miao J, et al. Pharmacokinetics and bioequivalence of two formulations of febuxostat 40-mg and 80-mg tablets: a randomized, open-label, 4-way crossover study in healthy Chinese male volunteers. PLoS One. 2016;11(3):e0150661. doi:10.1371/journal.pone.0150661\u003c/li\u003e\n\u003cli\u003eZhou H, Zheng Y, Wu G, et al. Pharmacokinetics and tolerability of febuxostat after oral administration in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose three-way crossover study. Int J Clin Pharmacol Ther. 2016;54(2):115\u0026ndash;124. doi:10.5414/CP202394\u003c/li\u003e\n\u003cli\u003eKamel B, Graham GG, Williams KM, et al. Clinical pharmacokinetics and pharmacodynamics of febuxostat. Clin Pharmacokinet. 2017;56(5):459\u0026ndash;475. doi:10.1007/s40262-016-0466-4\u003c/li\u003e\n\u003cli\u003eChen W, Jiang B, Ruan Z, et al. Population pharmacokinetic analysis of febuxostat with high focus on absorption kinetics and food effect. BMC Pharmacol Toxicol. 2024;25(1):57. doi:10.1186/s40360-024-00783-1\u003c/li\u003e\n\u003cli\u003eKamel B, Abuhelwa AY, Foster D, et al. Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout. Br J Clin Pharmacol. 2022;88(12):5359-5368. doi:10.1111/bcp.15462\u003c/li\u003e\n\u003cli\u003eWang C, Yu Q, Jiang X, et al. A drug-drug interaction study of a novel selective urate reabsorption inhibitor, SHR4640, and xanthine oxidase inhibitor, febuxostat, in patients with primary hyperuricemia. J Clin Pharmacol. 2023;63(2):239\u0026ndash;249. doi:10.1002/jcph.2159\u003c/li\u003e\n\u003cli\u003eGrabowski B, Khosravan R, Wu JT, et al. Effect of hydrochlorothiazide on the pharmacokinetics and pharmacodynamics of febuxostat, a non-purine selective inhibitor of xanthine oxidase. Br J Clin Pharmacol. 2010;70(1):57\u0026ndash;64. doi:10.1111/j.1365-2125.2010.03667.x\u003c/li\u003e\n\u003cli\u003eWorld Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191\u0026ndash;2194. doi:10.1001/jama.2013.281053\u003c/li\u003e\n\u003cli\u003eInternational Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed 24 Jan, 2025.\u003c/li\u003e\n\u003cli\u003eTakeda Pharmaceuticals USA. ULORIC (febuxostat) Tablets Prescribing Information. US Food and Drug Administration; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021856s013lbl.pdf. Accessed 20 Jan, 2025.\u003c/li\u003e\n\u003cli\u003eRekić D, Johansson S, Leander J. Higher febuxostat exposure observed in Asian compared with Caucasian subjects independent of bodyweight. Clin Pharmacokinet. 2021;60(3):319\u0026ndash;328. doi:10.1007/s40262-020-00943-6\u003c/li\u003e\n\u003cli\u003eChandu BR, Kanala K, Hwisa NT, et al. Bioequivalence and pharmacokinetic study of febuxostat in human plasma by using LC-MS/MS with liquid-liquid extraction method. Springerplus. 2013;2:194. doi:10.1186/2193-1801-2-194\u003c/li\u003e\n\u003cli\u003eUS Food and Drug Administration. Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. Center for Drug Evaluation and Research (CDER); 2022. https://www.fda.gov/media/70858/download. Accessed 22 Jan, 2025.\u003c/li\u003e\n\u003cli\u003eUS Food and Drug Administration. Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA. Center for Drug Evaluation and Research (CDER); 2021. https://www.fda.gov/media/87219/download. Accessed 20 Jan, 2025.\u003c/li\u003e\n\u003cli\u003eXu Y, Chen J, Yang D, et al. Development of LC-MS/MS determination method and backpropagation artificial neural networks pharmacokinetic model of febuxostat in healthy subjects. J Clin Pharm Ther. 2021;46(2):333\u0026ndash;342. doi:10.1111/jcpt.13285\u003c/li\u003e\n\u003cli\u003eWu Y, Mao Z, Liu Y, et al. Simultaneous determination of febuxostat and its three active metabolites in human plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study in Chinese healthy volunteers. J Pharm Biomed Anal. 2015;114:216\u0026ndash;221. doi:10.1016/j.jpba.2015.05.020\u003c/li\u003e\n\u003cli\u003eYu M, Li XB, Wang WP, et al. Pharmacokinetics study of single and multiple doses of febuxostat in Chinese healthy subjects [in Chinese]. Zhongguo Linchuang Yaolixue Zazhi [Chin J Clin Pharmacol]. 2023;39(5):723-727. doi:10.13699/j.cnki.1001-6821.2023.05.024\u003c/li\u003e\n\u003cli\u003eKhosravan R, Kukulka MJ, Wu JT, et al. The effect of age and gender on pharmacokinetics, pharmacodynamics, and safety of febuxostat, a novel nonpurine selective inhibitor of xanthine oxidase. J Clin Pharmacol. 2008;48(9):1014\u0026ndash;1024. doi:10.1177/0091270008322035\u003c/li\u003e\n\u003cli\u003eDeng J, Zhu X, Chen Z, et al. A review of food-drug interactions on oral drug absorption. Drugs. 2017;77(17):1833\u0026ndash;1855. doi:10.1007/s40265-017-0832-z\u003c/li\u003e\n\u003cli\u003eKhosravan R, Grabowski B, Wu JT, et al. Effect of food or antacid on pharmacokinetics and pharmacodynamics of febuxostat in healthy subjects. Br J Clin Pharmacol. 2008;65(3):355\u0026ndash;363. doi:10.1111/j.1365-2125.2007.03025.x\u003c/li\u003e\n\u003cli\u003eKamatani N, Fujimori S, Hada T, et al. Placebo-controlled, double-blind study of the non-purine-selective xanthine oxidase inhibitor febuxostat (TMX-67) in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol. 2011;17(4 Suppl):S19\u0026ndash;S26. doi:10.1097/RHU.0b013e31821d36de\u003c/li\u003e\n\u003cli\u003eTeijin Pharma Limited. Feburic\u003csup\u003e\u0026reg;\u003c/sup\u003e (febuxostat) Tablets Prescribing Information. Tokyo, Japan; 2023. https://www.pmda.go.jp/PmdaSearch/iyakuSearch/. Accessed 20 Jan, 2025.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"febuxostat, bioequivalence, pharmacokinetics, food effect, generic drug","lastPublishedDoi":"10.21203/rs.3.rs-6492168/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6492168/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFebuxostat, a xanthine oxidase inhibitor, is a first-line treatment for gout with hyperuricemia. This study evaluated the pharmacokinetic (PK) bioequivalence, safety profile, and food effects of a generic febuxostat formulation compared to the reference product (Feburic®) in healthy Chinese volunteers\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this randomized, open-label, two-sequence, two-period crossover trial, 80 participants (74 males, 6 females) received single 40 mg doses of both test and reference formulations under fasting and fed conditions, separated by a 7-day washout. Plasma concentrations were quantified using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Primary endpoints included peak plasma concentration (C\u003csub\u003emax\u003c/sub\u003e), area under the plasma concentration-time curve from time zero to the last time quantifiable time point (AUC\u003csub\u003e0 − t\u003c/sub\u003e ), and area under the plasma concentration-time curve from time zero to infinity (AUC\u003csub\u003e0−∞\u003c/sub\u003e), with bioequivalence determined using 90% confidence intervals (CIs) for geometric mean ratios (GMRs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll 90% CIs for GMRs fell within the 80–125% bioequivalence range (fasting: AUC\u003csub\u003e0 − t\u003c/sub\u003e 99.08-104.28%, AUC\u003csub\u003e0−∞\u003c/sub\u003e 98.73-103.84%, C\u003csub\u003emax\u003c/sub\u003e 92.87-112.14%; fed: AUC\u003csub\u003e0 − t\u003c/sub\u003e 101.16-106.21%, AUC\u003csub\u003e0−∞\u003c/sub\u003e 101.13-105.94%, C\u003csub\u003emax\u003c/sub\u003e 91.72-105.07%). High-fat meals delayed T\u003csub\u003emax\u003c/sub\u003e by 0.67 h (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05) and reduced systemic exposure (C\u003csub\u003emax\u003c/sub\u003e by ~ 35%, AUC\u003csub\u003e0−∞\u003c/sub\u003e by ~ 12%). Adverse event incidence was 12.8% (fasting) and 25.0% (fed), with no serious adverse events reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe generic febuxostat formulation demonstrated PK equivalence to Feburic® under both fasting and fed conditions, with comparable safety profiles. The observed food effects, while statistically significant, support flexible administration without meal restrictions, positioning this generic as a clinically equivalent, cost-effective alternative for gout management.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial Registration: \u003c/strong\u003eThis study was prospectively registered (Registration No. CTR20233483; First Public Release Date: 1 November 2023) in the Chinese Clinical Trial Registration Platform (http://www.chinadrugtrials.org.cn), a registry recognized by the Chinese National Medical Products Administration (NMPA). The trial was conducted from 28 November 2023 to 26 December 2023.\u003c/p\u003e","manuscriptTitle":"Bioequivalence Evaluation of Generic Febuxostat versus Feburic ® in Healthy Chinese Subjects: A Randomized Crossover Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-21 08:36:57","doi":"10.21203/rs.3.rs-6492168/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-05T11:25:15+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-03T13:46:39+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-21T12:20:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-21T10:49:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"10978648263518126839561482827485213293","date":"2025-05-18T09:06:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"3252942039645684811282323791064896795","date":"2025-05-16T09:13:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"110989535612519456859342627663623435048","date":"2025-05-16T08:02:59+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-16T07:05:51+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-06T15:22:20+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-22T07:44:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-22T07:40:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pharmacology and Toxicology","date":"2025-04-21T03:43:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pharmacology-and-toxicology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"phat","sideBox":"Learn more about [BMC Pharmacology and Toxicology](http://bmcpharmacoltoxicol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/phat/Default.aspx","title":"BMC Pharmacology and Toxicology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0506af36-444e-43e0-a43d-f694dd429e1d","owner":[],"postedDate":"May 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-13T16:00:09+00:00","versionOfRecord":{"articleIdentity":"rs-6492168","link":"https://doi.org/10.1186/s40360-025-01001-2","journal":{"identity":"bmc-pharmacology-and-toxicology","isVorOnly":false,"title":"BMC Pharmacology and Toxicology"},"publishedOn":"2025-10-06 15:57:21","publishedOnDateReadable":"October 6th, 2025"},"versionCreatedAt":"2025-05-21 08:36:57","video":"","vorDoi":"10.1186/s40360-025-01001-2","vorDoiUrl":"https://doi.org/10.1186/s40360-025-01001-2","workflowStages":[]},"version":"v1","identity":"rs-6492168","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6492168","identity":"rs-6492168","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}