Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial

Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial | 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 of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial Nan Mao, Zuoheng Xu, Jianfen Su, Bingna Wang, Diqun Zheng, Jianxing Liao, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4954921/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Dec, 2024 Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology → Version 1 posted 6 You are reading this latest preprint version Abstract Cefdinir is a broad-spectrum antibiotic with good antibacterial activity against gram-positive and gram-negative bacteria, and can be used for the treatment of various sensitive bacterial infections, such as community-acquired pneumonia, urinary tract infection and gonorrhea. Herein, a single-centred, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial with a 7-day washout was conducted to investigate the pharmacokinetics, bioequivalence and safety of cefdinir dispersible tablets and the reference formulation of cefdinir capsules in healthy Chinese volunteers. Fifty-six healthy subjects were recruited and randomly assigned to the fasting and fed groups. After a single oral dose of the test or reference formulation (0.1 g), the cefdinir concentrations in the plasma were determined via HPLC-MS/MS, and pharmacokinetic parameters were obtained from the concentration‒time profiles. Overall, 24 and 31 individuals completed the evaluation under fasting and fed conditions, respectively. The mean concentration‒time profiles for both formulations were similar, and the C max , AUC 0–t and AUC 0–∞ values were entirely within the bioequivalence range of 80.00–125.00%. 3 subjects reported 5 AEs and 8 subjects experienced 13 AEs in the fasting and fed group, respectively, but no participants withdrew from the trial because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The results demonstrated that these formulations were bioequivalent in healthy Chinese subjects under fasting and fed conditions, supporting the further clinical development of cefdinir dispersible tablets. This trial was registered in the China Drug Trials Registry (registration number: CTR20210441; registration date: March 11, 2021). bioequivalence healthy Chinese volunteers cefdinir dispersible tablets pharmacokinetics safety Figures Figure 1 Figure 2 Introduction Cefdinir (6R-[6a,7(Z)]-7)[[(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; FK482, BMY-28488. CI983, or PD134393) is an oral, extended-spectrum third-generation cephem antibiotic. Initially synthesized in 1988, cefdinir received approval from the United States Food and Drug Administration in 1997, specifically for the management of community-acquired infections(Chen et al., 2006 ). This pharmacological agent exhibits a broad range of activities against numerous pathogens, making it a significant option in the antimicrobial therapy arsenal(Guay, 2000 ). Cefdinir, which is structurally and functionally analogous to the orally administered cephalosporin cefixime, has enhanced in vitro antimicrobial efficacy against methicillin-sensitive Staphylococcus aureus and Staphylococcus epidermidis . It also exhibits potent activity against various strains of Streptococcus spp. and Neisseria spp. Such enhanced activity can be attributed to the presence of an oximino side chain at the 7-position, which is a substitute for the carboxymethoxyimino group commonly found in most orally active cephalosporins. This structural modification results in steric hindrance that impedes the entry of the molecule into the active site of the TEM-1 β-lactamase, thereby increasing its resistance to enzymatic degradation(J. Li et al., 2012 ). Cefdinir administration does not require consideration of food intake in drug instructions. The pharmacokinetic (PK) assessment following a single dose of 100 mg of cefdinir revealed several key parameters: the maximum plasma concentration (C max ) was 0.7 ± 0.19 µg/mL, the time to reach the maximum concentration (T max ) was 4.3 ± 0.5 h, the half-life (T 1/2 ) was 1.48 ± 0.12 h, and the area under the curve (AUC) from time zero to infinity (AUC 0−∞ ) was 4.04 ± 0.72 µg·h/mL. Moreover, healthy subjects demonstrated a renal clearance rate of 89.2 ± 6.0 mL/min. Furthermore, approximately 30.8 ± 8.2% of the administered dose was excreted unchanged in the urine within the first 24 h. These PK properties underscore the efficiency of renal excretion and drug bioavailability postadministration(Chen et al., 2006 ). The bioavailability of cefdinir has been estimated to be 21% for the 300 mg capsules and 16% for the 600 mg capsules. The absolute bioavailability of the suspension formulation is approximately 25%. PK studies have revealed that both the rate and extent of cefdinir absorption decrease when the drug is administered with a high-fat meal(Perry & Scott, 2004 ). The susceptibility of an organism to a specific dosing regimen of an agent can be determined as the highest minimum inhibitory concentration (MIC) for bacteriologic efficacy for that agent(Jacobs, 2003 ). Notably, PK and bioequivalence (BE) studies of cefdinir dispersible tablets in healthy Chinese volunteers are lacking to date, indicating a gap in the literature and a potential area for future research(Su H, & Guo RC, 2022). In this study, we aimed to evaluate the BE and safety of the generic drug cefdinir dispersible tablets and the branded drug cefdinir capsules (0.1 g) in healthy Chinese volunteers under fasting and fed conditions. Materials and Methods Product Source The test generic drug (T) of cefdinir dispersible tablets (specification: 0.1 g; batch number: 20093003; period of validity: September 11, 2020 to September 11, 2023) was produced by Guangdong BoZhou Pharmaceutical Co. Ltd. The branded drug of cefdinir capsules by Choseido Pharmaceutical Co., Ltd., Kawauchi Factory (trade name: Cefzon) (specification: 0.1 g; batch number: 1940C01, period of validity: October 21, 2019 to September 2021) was used as the reference product (R). Participants The primary inclusion and exclusion criteria for the study are detailed in the Supplementary Data Content (SDC) 1 . Vital sign measurements, including blood pressure, pulse, and temperature, along with inquiries regarding adverse events (AEs), were conducted at each cycle, specifically 0 h before dosing (within 1 h prior to administration) and at 1 ± 0.5 h, 4 ± 0.5 h, 10 ± 0.5 h, and 16 ± 1.0 h after dosing. On day 9 of the study, the participants underwent a 12-lead electrocardiogram (ECG) and comprehensive laboratory tests. All individuals participating in the study signed informed consent forms. Study Design This study was a single-centre, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial. Fasting and fed assessments were conducted in 56 cases. The participants were individually screened for each group and admitted to the hospital the day prior to drug administration, at which point they were randomly assigned to either the TR sequence or the RT sequence. Those in the TR group received the test drug during the first period and the reference drug during the second period, whereas those in the RT group received the drugs in the reverse order. The two study periods were interspersed with a 7-day washout period to clear any residual effects of the drugs before their subsequent administration. Randomization was performed with SAS software (version 9.4), which employs a 1:1 randomized block scheme to ensure equal distribution and reduce potential bias across treatment groups. All the participants fasted for at least 10 h. In the fasting arm, the participants received a single T or R drugs orally (0.1 g) with 240 mL of water. In the fed arm, participants consumed a standard high-fat breakfast of 800–1000 calories 30 min before each drug administration and followed the same schedule in subsequent periods. All the subjects were not allowed to drink water for 1 h before or after medication administration, and they fasted for 4 h after taking the medication. To minimize carryover effects between periods, there was a 7-day washout period. During the hospital-based study, participants were prohibited from engaging in rigorous exercise and were continuously monitored by experienced healthcare professionals. In accordance with the study protocol, researchers administered a standard lunch and dinner to participants in both groups following drug administration, ensuring consistency in dietary intake across the study population. The study was conducted according to Good Clinical Practice, the guidelines of the International Conference on Harmonization, and all applicable regulatory requirements. Blood Sampling A series of blood samples (4 mL) were collected at different time points: predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, and 16 h after each administration. EDTA-K2 was used as an anticoagulant. The vacuum blood collection tubes containing the blood samples were gently inverted 7–8 times, mixed well, and stored temporarily at 20–30°C. Bioanalytical Assay After the addition of the internal standard (IS) cefdinir 15N2, 13C, the plasma concentrations of the test and reference products were quantified via protein precipitation and high performance liquid chromatography–tandem mass spectrometry (HPLC‒MS/MS). The blood samples were centrifuged at 1700 × g for 10 min at 4°C (1–9°C). The supernatant was then separated into 2 parts for drug monitoring and reserve. Before the plasma samples were transferred to the refrigerator, they were placed at 1°C to 9°C (wet ice, ice‒water mixture). The centrifuged plasma samples were placed in a sample cryobox within 2 h after blood collection and stored at -10°C to -30°C or below until sample transportation. Bioanalysis was performed via a Shimadzu high-performance liquid chromatography (HPLC) 30-AD system linked to an API 6500 + Applied Biosystems Tandem quadrupole mass spectrometer. Chromatographic separation was conducted on an ACE Excel 3 C18 column (50 × 2.1 mm). Formic acid (0.4%) (phase A) and methyl formic acid (0.4%): acetonitrile formate (0.4%) (1:2) (phase B) were used as the mobile phases. Gradient elution was performed for chromatographic separation at a flow rate of 0.5 mL/min as follows: 0.00–0.49 mi (5% B), 2.40–2.99 min (100% B), and 3.00–3.99 min (5% B). Cefdinir 15N2, 13C was used as the IS. The mode of ionization was positive electrospray ((+) ES), the mode of scanning was multiple reaction monitoring (MRM), and the time of acquisition was 4 min. The MRM transitions of cefdinir and the IS were m/z 396.1→227.0 and m/z 399.0→230.1, respectively. The linearity was in the range of 10.0–5000 ng/mL. The intra- and interbatch precision values for cefdinir were < 7.02%. The IS-normalized recovery was 88.60%. Sample Preparation For the plasma samples, 50 µL of plasma was added to 20 µL of IS and extracted with 500 µL of methanol. The samples were subsequently centrifuged at 4°C for 5 min at 3200 × g. Finally, the supernatant (200 µL) was injected onto the HPLC–MS system for analysis. PK Analysis In this investigation, the PK parameters of cefdinir, such as the area under the plasma concentration‒time curve from time 0 to the last quantifiable concentration (AUC 0–t ) and AUC 0∞ , C max , T max , and elimination T 1/2 , were quantified. Moreover, the within-subject variability for both the reference and test formulations of the drug was evaluated. These parameters were calculated via the noncompartmental analysis method in Phoenix WinNonlin software, version 8.1. AUC calculations were conducted employing the linear trapezoidal interpolation technique. For statistical analysis and descriptive statistics, SAS software version 9.4 (SAS Institute) was utilized. BE Assessment On the basis of the BE set, analysis of variance was performed after the logarithmic transformation of C max, AUC 0–t and AUC 0–∞ to assess the sequence. If the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) (T/R) for C max, AUC 0–t and AUC 0–∞ were within 80–125% of the statistical interval, the 2 drugs were considered bioequivalent. Data processing and statistical analyses were performed with SAS version 9.4. Safety Assessment During the study, safety and tolerability were assessed on the basis of AEs, physical examinations, vital signs, 12-lead ECGs, and clinical laboratory tests. The causal relationships between AEs and investigational products were assessed. The monitored vital signs included blood pressure, pulse, and temperature. In addition, clinical laboratory tests, including haematology, biochemistry, coagulation, urinalysis, and pregnancy tests, were performed to evaluate the safety of the interventions in the participants. Results Study Population Of the 140 subjects who were screened, 84 experienced screen failure. Thirty-two subjects were included in the fed study, and 24 subjects were included in the fasting study; overall, 54 participants completed the whole study, shown in Fig. 1 . The demographic characteristics of the TRTR and RTRT sequences for each condition were comparable. The detailed demographic characteristics of the enrolled subjects are shown in Table 1 . The demographic characteristics of the participants in each group are shown in Table S1 . Table 1 Demographic characteristics of the enrolled subjects Characteristic Fasting (N = 24) Fed (N = 32) Male 22 (91.70%) 23 (71.90%) Female 2 (8.30%) 9 (28.10%) Age (years) 28.8 (± 5.47) 29.0 (± 5.67) Height (cm) 168.33 (± 6.95) 165.33 (± 7.79) Weight (kg) 63.02 (± 8.12) 59.90 (± 7.43) BMI (kg/m 2 ) 22.17 (± 1.79) 21.85 (± 1.66) N, indicates the number of participants in the calculation. PK Properties The mean plasma concentration–time curves constructed after a single oral dose of cefdinir dispersible tablets was administered to the subjects in the fasted and fed states are shown in Fig. 2 . The PK parameters for the test and reference products are summarized in Table 2 . As shown in the figure, in both the fasting and fed studies, the mean plasma concentration–time curves of the test and reference preparations essentially overlapped. Additionally, the C max , AUC 0–t and AUC 0–∞ values in the fed state were significantly lower than those in the fasted state, indicating that food could interfere with the absorption of these two drugs. Table 2 Pharmacokinetic parameters under fasting and fed conditions Mean ± SD Parameter Fasting (N = 24) Fed (N = 32) Test Reference Test Reference T max (h) 3.67 ± 0.87 3.80 ± 0.91 3.89 ± 0.93 4.52 ± 0.74 C max (ng/mL) 1182.87 ± 373.85 1120.35 ± 404.29 753.97 ± 163.35 742.06 ± 206.32 AUC 0–t (ng·h/mL) 6518.15 ± 2453.89 6296.73 ± 2462.76 4330.77 ± 989.98 4536.84 ± 1171.11 AUC 0–∞ (ng·h/mL) 6565.25 ± 2484.51 6351.57 ± 2492.65 4384.53 ± 1005.49 4635.35 ± 1215.65 T 1/2 (h) 1.76 ± 0.18 1.73 ± 0.19 1.80 ± 0.31 1.85 ± 0.53 Data are expressed as mean ± standard deviation; N, indicates the number of participants in the calculation; C max : maximum blood concentration; T max , time to reach maximum blood concentration; AUC 0 − t , the area under the curve from time 0 (baseline) to time t; AUC 0 − ∞ , the area under the curve from 0 to infinity; T 1/2 , half-life of elimination. Table 3 Bioequivalence under fasting and fed conditions Fasting (N = 24) Fed (N = 32) PK Parameters GMR (%) CV (%) 90% CI for GMR (%) GMR (%) CV (%) 90% CI for GMR (%) C max (ng/mL) 106.74 18.48 97.29–117.10 102.99 11.87 97.86-108.39 AUC 0–t (ng·h/mL) 103.55 22.71 92.46-115.98 96.44 9.95 92.40-100.67 AUC 0–∞ (ng·h/mL) 103.41 22.52 92.41-115.71 95.65 10.68 91.35-100.15 N, indicates the number of participants in the calculation; C max : maximum blood concentration; AUC 0 − t , the area under the curve from time 0 (baseline) to time t; AUC 0 − ∞ , the area under the curve from 0 to infinity; CV%, the variability within the volunteer; GM, the geometric mean value; F(%), the ratio of (T/R) geometric mean; 90% CI, 90% confidence interval;. Safety and Tolerability Among the 24 subjects included in the safety analysis under fasting conditions in the BE trials, 3 experienced 5 AEs, but no subjects withdrew from the test because of AEs. In the fed test, 8 subjects experienced 13 AEs, but no subjects withdrew because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The most common AEs in the fasted and fed groups were positive urine occult blood and positive urine white blood cells. Overall, the treatments were safe and well tolerated. The incidence of AEs is summarized in Table S3. Discussion Cefdinir is an oral broad-spectrum third-generation cephalosporins that function as penicillin-like bactericidal agents that inhibit bacterial cell wall synthesis. The oral bioavailability of it is enhanced by the presence of a vinyl moiety at position 3 of the cephalosporin nucleus(Bansal, Aggarwal, Chandel, & Harikumar, 2013 ). Cefdinir has high efficacy against various gram-positive and gram-negative bacteria(Khan et al., 2011 ), making it suitable for treating conditions such as otitis media(Adler, McDonald, Trostmann, Keyserling, & Tack, 2000 ), soft tissue infections(Lin, Lin, Tsai, Wang, & Chi, 2021 ), and respiratory tract infections(Sader & Jones, 2007 ), including sinusitis, community-acquired pneumonia, and acute exacerbations of bronchitis. The absolute oral bioavailability of cefdinir has been reported to be only 21–25% (Perry and Scott, 2004 ), which is due mainly to its poor aqueous solubility(Khan et al., 2011 ). Studies have proven that there is no significant difference in the clinical efficacy and safety of patients using cefdinir dispersible tablets and original cefdinir capsules(Wang Z, et al., 2023 ). However, the PK profile and bioequivalence of cefdinir dispersible tablets compared original cefdinir capsules under fasting and fed conditions in healthy Chinese subjects has not been reported. In the fasting groups, the PK parameters of both products were similar. However, under fasting conditions, the PK parameters in the reference group were slightly lower than those in the test group. Comparing with the fasting state, the C max , AUC 0–t , AUC 0–∞ and T max of test and reference group were significantly decreased in the fed state, indicating that the food reduced the absorption rate of the active ingredient in cefdinir dispersible tablets and cefdinir capsules, thereby affecting the bioavailability. Under the same conditions, the T max and T 1/2 of the reference preparation were prolonged, whereas the test preparation had no significant change, suggesting that food only significantly delay the absorption rate of cefdinir capsules and has no effect on that of cefdinir tablets. These results suggest that interactions between food and this medicine affect drug bioavailability and that a high-calorie, high-fat diet is more likely to alter the physiological properties of the gastrointestinal tract and thus have a greater effect on drug bioavailability. The bioavailability of cefdinir is estimated to be 21% for the 300 mg capsules and 16% for the 600 mg capsules, with the suspension formulation exhibiting an absolute bioavailability of 25%. Studies indicate that both the rate and extent of cefdinir absorption are reduced when a high-fat meal is consumed 3 . This study further confirmed that a high-fat meal significantly altered the PK profile of cefdinir dispersible tablets in healthy Chinese subjects, which aligns with findings from previous studies. According to these guidelines, the cleaning period generally more than seven times the half-life of the test doses(Xu et al., 2023 ; Zhang et al., 2023 ). According to the instructions, the T 1/2 of cefdinir is about 1.6 to 1.8h, so it is reasonable for this study to set the cleaning cycle (dosing interval) to 7 days, which is more than 7 times the T 1/2 . Intrasubject variability of preparations for PK parameters (C max , AUC 0 − t , and AUC 0−∞ ) exceeding 30% are considered highly variable drugs(Z. Li et al., 2021 ; Su et al., 2023 ). Based on the Table 3 , the CV (%) of cefdinir preparations for PK parameters were less than 30%, indicating that neither cefdinir dispersible tablets nor cefdinir capsules was a highly variable drug. The BE analysis revealed that the 90% CIs of the GMR (T/R) of both formulations were in the range of 80–125% after logarithmic conversion, suggesting that the test and reference cefdinir tablets were bioequivalent. Moreover, the safety evaluation revealed that cefdinir dispersible tablets were safe and well tolerated. A total of 18 AEs were reported, all of which were grade I in severity, and there were no serious AEs or deaths. In summary, the text and reference formulations were bioequivalent, with no observable safety differences in the fasting/fed state. Conclusion The results of the present study revealed that the test cefdinir dispersible tablets were bioequivalent to the reference formulation in healthy Chinese subjects under both fasting and fed states, and the safety profiles of the test and reference formulations were similar. The absorption of both the test and reference formulations was affected by the ingestion of food. On the basis of these PK features, the cefdinir dispersal tablets, produced by Guangdong BoZhou Pharmaceutical Co., Ltd., is expected to be an alternative option to the reference tablet. Declarations Acknowledgements The authors are grateful to the volunteers in this study and the Phase I Clinical Trial Center team members of Panyu Central Hospital. Authors contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Z.X. and J.S.. The original draft of the manuscript was written by N.M. and B.W., with additional review and editing by X.L.. The inspection of sample testing process, data, report and calculation process was conducted by D.Z. and J.L.. All authors commented on previous versions of the manuscript and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used. Funding This work was supported by Guangdong Basic and Applied Basic Research Fund Enterprise Joint Fund [grant numbers 2023A1515220024], Medical Research Foundation of Guangdong Province [grant numbers 2024070], Guangdong Hospital Pharmaceutical Research Fund project funding [grant numbers 2024A31], the Research Funds from Guangzhou Panyu Central Hospital [grant numbers PY-2023-007, PY-2023-010, PY-2023-026]. Data availability Data are availability from corresponding author upon reasonable request but remain subject to all applicable legal requirements to protect the confdentiality of the study participants’ personal information. Ethical approval This clinical trial was registered in the China Drug Trials Registry (http://www.chinadrugtrials.org.cn; registration number: CTR20210441; registration date: March 11, 2021). It was approved by the Ethics Committee of Panyu Central Hospital (Clinical Research Ethics Committee approval number: PYZXYYEC【2020-029】) and was conducted independently at the Phase I Clinical Trial Research Center of Panyu Central Hospital from March 15, 2021 to April 12, 2021. This study complied with the requirements of the Declaration of Helsinki (1989), Guidelines of Good Clinical Practice, and other related guiding principles. Consent to participate Informed consent was obtained from all individual participants included in the trial. 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Supplementary Files file.docx Cite Share Download PDF Status: Published Journal Publication published 16 Dec, 2024 Read the published version in Naunyn-Schmiedeberg's Archives of Pharmacology → Version 1 posted Reviews received at journal 19 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers invited by journal 03 Sep, 2024 Editor assigned by journal 22 Aug, 2024 Submission checks completed at journal 22 Aug, 2024 First submitted to journal 22 Aug, 2024 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-4954921","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":356530580,"identity":"35f02079-7c83-4a90-bdde-8fbb63918953","order_by":0,"name":"Nan Mao","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nan","middleName":"","lastName":"Mao","suffix":""},{"id":356530583,"identity":"dbfa74e9-4a6d-4d8c-9189-30e75660760a","order_by":1,"name":"Zuoheng Xu","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zuoheng","middleName":"","lastName":"Xu","suffix":""},{"id":356530587,"identity":"0f96dc68-1c45-420a-8a75-b4e11776aaa7","order_by":2,"name":"Jianfen Su","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jianfen","middleName":"","lastName":"Su","suffix":""},{"id":356530589,"identity":"c0892e34-3398-4e45-a6e6-608837370b3e","order_by":3,"name":"Bingna Wang","email":"","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bingna","middleName":"","lastName":"Wang","suffix":""},{"id":356530590,"identity":"19160489-97f7-42b6-b2dd-ea03a64955f3","order_by":4,"name":"Diqun Zheng","email":"","orcid":"","institution":"Guangdong Bozhou Pharmaceutical Co., LTD","correspondingAuthor":false,"prefix":"","firstName":"Diqun","middleName":"","lastName":"Zheng","suffix":""},{"id":356530592,"identity":"341fca8a-8dbc-4f4b-9e24-4ba0a3c3d9ac","order_by":5,"name":"Jianxing Liao","email":"","orcid":"","institution":"Guangdong Bozhou Pharmaceutical Co., LTD","correspondingAuthor":false,"prefix":"","firstName":"Jianxing","middleName":"","lastName":"Liao","suffix":""},{"id":356530595,"identity":"556d50bd-01e0-476c-88c6-dfdce5d862dd","order_by":6,"name":"Xiaoyan Liu","email":"data:image/png;base64,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","orcid":"","institution":"Guangzhou Panyu Central Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-08-22 04:04:03","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4954921/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4954921/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00210-024-03701-8","type":"published","date":"2024-12-16T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":66663949,"identity":"535a7d89-d665-4009-8302-d60c62b7bd24","added_by":"auto","created_at":"2024-10-15 09:13:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46135,"visible":true,"origin":"","legend":"\u003cp\u003eTrial profile.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4954921/v1/67d3b5697fbd67b7fd15c3ec.png"},{"id":66663951,"identity":"97962414-1538-444c-ab6d-c2cf7d93e577","added_by":"auto","created_at":"2024-10-15 09:13:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":84518,"visible":true,"origin":"","legend":"\u003cp\u003eConcentration‒time profiles (means±±SEs). (A) Mean plasma concentration–time profiles in the fasting arm; and (B) mean plasma concentration–time profiles in the fed arm. R, reference; T, test.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4954921/v1/7491dedff98ab35c94f86aac.png"},{"id":72202063,"identity":"fce7e956-4322-4612-af1c-d4cc6c2b36c2","added_by":"auto","created_at":"2024-12-23 16:14:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":608295,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4954921/v1/73880a1a-3373-439b-9f34-baebebd58980.pdf"},{"id":66663950,"identity":"3f3e1a49-19f8-4582-9dd5-a38a70bfd579","added_by":"auto","created_at":"2024-10-15 09:13:33","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":20470,"visible":true,"origin":"","legend":"","description":"","filename":"file.docx","url":"https://assets-eu.researchsquare.com/files/rs-4954921/v1/bab6b7fdf86e71e074bff57f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCefdinir (6R-[6a,7(Z)]-7)[[(2-amino-4-thiazolyl)(hydroxyimino)acetyl]amino]-3-ethenyl-8-oxo-5-thia-lazabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; FK482, BMY-28488. CI983, or PD134393) is an oral, extended-spectrum third-generation cephem antibiotic. Initially synthesized in 1988, cefdinir received approval from the United States Food and Drug Administration in 1997, specifically for the management of community-acquired infections(Chen et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2006\u003c/span\u003e). This pharmacological agent exhibits a broad range of activities against numerous pathogens, making it a significant option in the antimicrobial therapy arsenal(Guay, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2000\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCefdinir, which is structurally and functionally analogous to the orally administered cephalosporin cefixime, has enhanced in vitro antimicrobial efficacy against methicillin-sensitive \u003cem\u003eStaphylococcus aureus\u003c/em\u003e and \u003cem\u003eStaphylococcus epidermidis\u003c/em\u003e. It also exhibits potent activity against various strains of Streptococcus spp. and Neisseria spp. Such enhanced activity can be attributed to the presence of an oximino side chain at the 7-position, which is a substitute for the carboxymethoxyimino group commonly found in most orally active cephalosporins. This structural modification results in steric hindrance that impedes the entry of the molecule into the active site of the TEM-1 β-lactamase, thereby increasing its resistance to enzymatic degradation(J. Li et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eCefdinir administration does not require consideration of food intake in drug instructions. The pharmacokinetic (PK) assessment following a single dose of 100 mg of cefdinir revealed several key parameters: the maximum plasma concentration (C\u003csub\u003emax\u003c/sub\u003e) was 0.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 \u0026micro;g/mL, the time to reach the maximum concentration (T\u003csub\u003emax\u003c/sub\u003e) was 4.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 h, the half-life (T\u003csub\u003e1/2\u003c/sub\u003e) was 1.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12 h, and the area under the curve (AUC) from time zero to infinity (AUC\u003csub\u003e0\u0026minus;\u0026infin;\u003c/sub\u003e) was 4.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72 \u0026micro;g\u0026middot;h/mL. Moreover, healthy subjects demonstrated a renal clearance rate of 89.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 mL/min. Furthermore, approximately 30.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2% of the administered dose was excreted unchanged in the urine within the first 24 h. These PK properties underscore the efficiency of renal excretion and drug bioavailability postadministration(Chen et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2006\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe bioavailability of cefdinir has been estimated to be 21% for the 300 mg capsules and 16% for the 600 mg capsules. The absolute bioavailability of the suspension formulation is approximately 25%. PK studies have revealed that both the rate and extent of cefdinir absorption decrease when the drug is administered with a high-fat meal(Perry \u0026amp; Scott, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). The susceptibility of an organism to a specific dosing regimen of an agent can be determined as the highest minimum inhibitory concentration (MIC) for bacteriologic efficacy for that agent(Jacobs, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Notably, PK and bioequivalence (BE) studies of cefdinir dispersible tablets in healthy Chinese volunteers are lacking to date, indicating a gap in the literature and a potential area for future research(Su H, \u0026amp; Guo RC, 2022).\u003c/p\u003e \u003cp\u003eIn this study, we aimed to evaluate the BE and safety of the generic drug cefdinir dispersible tablets and the branded drug cefdinir capsules (0.1 g) in healthy Chinese volunteers under fasting and fed conditions.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eProduct Source\u003c/h2\u003e \u003cp\u003eThe test generic drug (T) of cefdinir dispersible tablets (specification: 0.1 g; batch number: 20093003; period of validity: September 11, 2020 to September 11, 2023) was produced by Guangdong BoZhou Pharmaceutical Co. Ltd. The branded drug of cefdinir capsules by Choseido Pharmaceutical Co., Ltd., Kawauchi Factory (trade name: Cefzon) (specification: 0.1 g; batch number: 1940C01, period of validity: October 21, 2019 to September 2021) was used as the reference product (R).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eThe primary inclusion and exclusion criteria for the study are detailed in the Supplementary Data Content (SDC) \u003csup\u003e1\u003c/sup\u003e. Vital sign measurements, including blood pressure, pulse, and temperature, along with inquiries regarding adverse events (AEs), were conducted at each cycle, specifically 0 h before dosing (within 1 h prior to administration) and at 1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 h, 4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 h, 10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5 h, and 16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 h after dosing. On day 9 of the study, the participants underwent a 12-lead electrocardiogram (ECG) and comprehensive laboratory tests. All individuals participating in the study signed informed consent forms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design\u003c/h2\u003e \u003cp\u003eThis study was a single-centre, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial. Fasting and fed assessments were conducted in 56 cases. The participants were individually screened for each group and admitted to the hospital the day prior to drug administration, at which point they were randomly assigned to either the TR sequence or the RT sequence. Those in the TR group received the test drug during the first period and the reference drug during the second period, whereas those in the RT group received the drugs in the reverse order. The two study periods were interspersed with a 7-day washout period to clear any residual effects of the drugs before their subsequent administration. Randomization was performed with SAS software (version 9.4), which employs a 1:1 randomized block scheme to ensure equal distribution and reduce potential bias across treatment groups.\u003c/p\u003e \u003cp\u003e All the participants fasted for at least 10 h. In the fasting arm, the participants received a single T or R drugs orally (0.1 g) with 240 mL of water. In the fed arm, participants consumed a standard high-fat breakfast of 800\u0026ndash;1000 calories 30 min before each drug administration and followed the same schedule in subsequent periods. All the subjects were not allowed to drink water for 1 h before or after medication administration, and they fasted for 4 h after taking the medication. To minimize carryover effects between periods, there was a 7-day washout period. During the hospital-based study, participants were prohibited from engaging in rigorous exercise and were continuously monitored by experienced healthcare professionals. In accordance with the study protocol, researchers administered a standard lunch and dinner to participants in both groups following drug administration, ensuring consistency in dietary intake across the study population.\u003c/p\u003e \u003cp\u003e The study was conducted according to Good Clinical Practice, the guidelines of the International Conference on Harmonization, and all applicable regulatory requirements.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eBlood Sampling\u003c/h2\u003e \u003cp\u003eA series of blood samples (4 mL) were collected at different time points: predose and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, and 16 h after each administration. EDTA-K2 was used as an anticoagulant. The vacuum blood collection tubes containing the blood samples were gently inverted 7\u0026ndash;8 times, mixed well, and stored temporarily at 20\u0026ndash;30\u0026deg;C.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eBioanalytical Assay\u003c/h2\u003e \u003cp\u003eAfter the addition of the internal standard (IS) cefdinir 15N2, 13C, the plasma concentrations of the test and reference products were quantified via protein precipitation and high performance liquid chromatography\u0026ndash;tandem mass spectrometry (HPLC‒MS/MS).\u003c/p\u003e \u003cp\u003eThe blood samples were centrifuged at 1700 \u0026times; g for 10 min at 4\u0026deg;C (1\u0026ndash;9\u0026deg;C). The supernatant was then separated into 2 parts for drug monitoring and reserve. Before the plasma samples were transferred to the refrigerator, they were placed at 1\u0026deg;C to 9\u0026deg;C (wet ice, ice‒water mixture). The centrifuged plasma samples were placed in a sample cryobox within 2 h after blood collection and stored at -10\u0026deg;C to -30\u0026deg;C or below until sample transportation. Bioanalysis was performed via a Shimadzu high-performance liquid chromatography (HPLC) 30-AD system linked to an API 6500\u0026thinsp;+\u0026thinsp;Applied Biosystems Tandem quadrupole mass spectrometer. Chromatographic separation was conducted on an ACE Excel 3 C18 column (50 \u0026times; 2.1 mm). Formic acid (0.4%) (phase A) and methyl formic acid (0.4%): acetonitrile formate (0.4%) (1:2) (phase B) were used as the mobile phases. Gradient elution was performed for chromatographic separation at a flow rate of 0.5 mL/min as follows: 0.00\u0026ndash;0.49 mi (5% B), 2.40\u0026ndash;2.99 min (100% B), and 3.00\u0026ndash;3.99 min (5% B). Cefdinir 15N2, 13C was used as the IS. The mode of ionization was positive electrospray ((+) ES), the mode of scanning was multiple reaction monitoring (MRM), and the time of acquisition was 4 min. The MRM transitions of cefdinir and the IS were m/z 396.1\u0026rarr;227.0 and m/z 399.0\u0026rarr;230.1, respectively. The linearity was in the range of 10.0\u0026ndash;5000 ng/mL. The intra- and interbatch precision values for cefdinir were \u0026lt;\u0026thinsp;7.02%. The IS-normalized recovery was 88.60%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSample Preparation\u003c/h2\u003e \u003cp\u003eFor the plasma samples, 50 \u0026micro;L of plasma was added to 20 \u0026micro;L of IS and extracted with 500 \u0026micro;L of methanol. The samples were subsequently centrifuged at 4\u0026deg;C for 5 min at 3200 \u0026times; g. Finally, the supernatant (200 \u0026micro;L) was injected onto the HPLC\u0026ndash;MS system for analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePK Analysis\u003c/h2\u003e \u003cp\u003eIn this investigation, the PK parameters of cefdinir, such as the area under the plasma concentration‒time curve from time 0 to the last quantifiable concentration (AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e) and AUC\u003csub\u003e0\u0026infin;\u003c/sub\u003e, C\u003csub\u003emax\u003c/sub\u003e, T\u003csub\u003emax\u003c/sub\u003e, and elimination T\u003csub\u003e1/2\u003c/sub\u003e, were quantified. Moreover, the within-subject variability for both the reference and test formulations of the drug was evaluated. These parameters were calculated via the noncompartmental analysis method in Phoenix WinNonlin software, version 8.1. AUC calculations were conducted employing the linear trapezoidal interpolation technique. For statistical analysis and descriptive statistics, SAS software version 9.4 (SAS Institute) was utilized.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eBE Assessment\u003c/h2\u003e \u003cp\u003eOn the basis of the BE set, analysis of variance was performed after the logarithmic transformation of C\u003csub\u003emax,\u003c/sub\u003e AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e to assess the sequence. If the 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) (T/R) for C\u003csub\u003emax,\u003c/sub\u003e AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e were within 80\u0026ndash;125% of the statistical interval, the 2 drugs were considered bioequivalent. Data processing and statistical analyses were performed with SAS version 9.4.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety Assessment\u003c/h2\u003e \u003cp\u003eDuring the study, safety and tolerability were assessed on the basis of AEs, physical examinations, vital signs, 12-lead ECGs, and clinical laboratory tests. The causal relationships between AEs and investigational products were assessed. The monitored vital signs included blood pressure, pulse, and temperature. In addition, clinical laboratory tests, including haematology, biochemistry, coagulation, urinalysis, and pregnancy tests, were performed to evaluate the safety of the interventions in the participants.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStudy Population\u003c/h2\u003e \u003cp\u003eOf the 140 subjects who were screened, 84 experienced screen failure. Thirty-two subjects were included in the fed study, and 24 subjects were included in the fasting study; overall, 54 participants completed the whole study, shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The demographic characteristics of the TRTR and RTRT sequences for each condition were comparable. The detailed demographic characteristics of the enrolled subjects are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The demographic characteristics of the participants in each group are shown in Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic characteristics of the enrolled subjects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFasting (N\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFed (N\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22 (91.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23 (71.90%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (8.30%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9 (28.10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28.8 (\u0026plusmn;\u0026thinsp;5.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29.0 (\u0026plusmn;\u0026thinsp;5.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e168.33 (\u0026plusmn;\u0026thinsp;6.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e165.33 (\u0026plusmn;\u0026thinsp;7.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63.02 (\u0026plusmn;\u0026thinsp;8.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59.90 (\u0026plusmn;\u0026thinsp;7.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.17 (\u0026plusmn;\u0026thinsp;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21.85 (\u0026plusmn;\u0026thinsp;1.66)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eN, indicates the number of participants in the calculation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePK Properties\u003c/h2\u003e \u003cp\u003eThe mean plasma concentration\u0026ndash;time curves constructed after a single oral dose of cefdinir dispersible tablets was administered to the subjects in the fasted and fed states are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The PK parameters for the test and reference products are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. As shown in the figure, in both the fasting and fed studies, the mean plasma concentration\u0026ndash;time curves of the test and reference preparations essentially overlapped. Additionally, the C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e values in the fed state were significantly lower than those in the fasted state, indicating that food could interfere with the absorption of these two drugs.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePharmacokinetic parameters under fasting and fed conditions\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eFasting (N\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eFed (N\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003emax\u003c/sub\u003e (h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.89\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1182.87\u0026thinsp;\u0026plusmn;\u0026thinsp;373.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1120.35\u0026thinsp;\u0026plusmn;\u0026thinsp;404.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e753.97\u0026thinsp;\u0026plusmn;\u0026thinsp;163.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e742.06\u0026thinsp;\u0026plusmn;\u0026thinsp;206.32\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e (ng\u0026middot;h/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6518.15\u0026thinsp;\u0026plusmn;\u0026thinsp;2453.89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6296.73\u0026thinsp;\u0026plusmn;\u0026thinsp;2462.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4330.77\u0026thinsp;\u0026plusmn;\u0026thinsp;989.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4536.84\u0026thinsp;\u0026plusmn;\u0026thinsp;1171.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e (ng\u0026middot;h/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6565.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2484.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6351.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2492.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4384.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1005.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4635.35\u0026thinsp;\u0026plusmn;\u0026thinsp;1215.65\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT\u003csub\u003e1/2\u003c/sub\u003e (h)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.76\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.73\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.85\u0026thinsp;\u0026plusmn;\u0026thinsp;0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eData are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation; N, indicates the number of participants in the calculation; C\u003csub\u003emax\u003c/sub\u003e: maximum blood concentration; T\u003csub\u003emax\u003c/sub\u003e, time to reach maximum blood concentration; AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, the area under the curve from time 0 (baseline) to time t; AUC\u003csub\u003e0 \u0026minus; \u0026infin;\u003c/sub\u003e, the area under the curve from 0 to infinity; T\u003csub\u003e1/2\u003c/sub\u003e, half-life of elimination.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBioequivalence under fasting and fed conditions\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eFasting (N\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eFed (N\u0026thinsp;=\u0026thinsp;32)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePK\u003c/p\u003e \u003cp\u003eParameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGMR (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCV (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e90% CI for GMR (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGMR (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCV (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e90% CI for GMR (%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC\u003csub\u003emax\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e(ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e106.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18.48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97.29\u0026ndash;117.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e102.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e97.86-108.39\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e (ng\u0026middot;h/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92.46-115.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e9.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e92.40-100.67\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e (ng\u0026middot;h/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e103.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92.41-115.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e91.35-100.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eN, indicates the number of participants in the calculation; C\u003csub\u003emax\u003c/sub\u003e: maximum blood concentration; AUC\u003csub\u003e0\u0026thinsp;\u0026minus;\u0026thinsp;t\u003c/sub\u003e, the area under the curve from time 0 (baseline) to time t; AUC\u003csub\u003e0 \u0026minus; \u0026infin;\u003c/sub\u003e, the area under the curve from 0 to infinity; CV%, the variability within the volunteer; GM, the geometric mean value; F(%), the ratio of (T/R) geometric mean; 90% CI, 90% confidence interval;.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSafety and Tolerability\u003c/h2\u003e \u003cp\u003eAmong the 24 subjects included in the safety analysis under fasting conditions in the BE trials, 3 experienced 5 AEs, but no subjects withdrew from the test because of AEs. In the fed test, 8 subjects experienced 13 AEs, but no subjects withdrew because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The most common AEs in the fasted and fed groups were positive urine occult blood and positive urine white blood cells. Overall, the treatments were safe and well tolerated. The incidence of AEs is summarized in Table S3.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCefdinir is an oral broad-spectrum third-generation cephalosporins that function as penicillin-like bactericidal agents that inhibit bacterial cell wall synthesis. The oral bioavailability of it is enhanced by the presence of a vinyl moiety at position 3 of the cephalosporin nucleus(Bansal, Aggarwal, Chandel, \u0026amp; Harikumar, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). Cefdinir has high efficacy against various gram-positive and gram-negative bacteria(Khan et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), making it suitable for treating conditions such as otitis media(Adler, McDonald, Trostmann, Keyserling, \u0026amp; Tack, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2000\u003c/span\u003e), soft tissue infections(Lin, Lin, Tsai, Wang, \u0026amp; Chi, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), and respiratory tract infections(Sader \u0026amp; Jones, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2007\u003c/span\u003e), including sinusitis, community-acquired pneumonia, and acute exacerbations of bronchitis. The absolute oral bioavailability of cefdinir has been reported to be only 21\u0026ndash;25% (Perry and Scott, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2004\u003c/span\u003e), which is due mainly to its poor aqueous solubility(Khan et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). Studies have proven that there is no significant difference in the clinical efficacy and safety of patients using cefdinir dispersible tablets and original cefdinir capsules(Wang Z, et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). However, the PK profile and bioequivalence of cefdinir dispersible tablets compared original cefdinir capsules under fasting and fed conditions in healthy Chinese subjects has not been reported.\u003c/p\u003e \u003cp\u003eIn the fasting groups, the PK parameters of both products were similar. However, under fasting conditions, the PK parameters in the reference group were slightly lower than those in the test group. Comparing with the fasting state, the C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e, AUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e and T\u003csub\u003emax\u003c/sub\u003e of test and reference group were significantly decreased in the fed state, indicating that the food reduced the absorption rate of the active ingredient in cefdinir dispersible tablets and cefdinir capsules, thereby affecting the bioavailability. Under the same conditions, the T\u003csub\u003emax\u003c/sub\u003e and T\u003csub\u003e1/2\u003c/sub\u003e of the reference preparation were prolonged, whereas the test preparation had no significant change, suggesting that food only significantly delay the absorption rate of cefdinir capsules and has no effect on that of cefdinir tablets. These results suggest that interactions between food and this medicine affect drug bioavailability and that a high-calorie, high-fat diet is more likely to alter the physiological properties of the gastrointestinal tract and thus have a greater effect on drug bioavailability. The bioavailability of cefdinir is estimated to be 21% for the 300 mg capsules and 16% for the 600 mg capsules, with the suspension formulation exhibiting an absolute bioavailability of 25%. Studies indicate that both the rate and extent of cefdinir absorption are reduced when a high-fat meal is consumed\u003csup\u003e3\u003c/sup\u003e. This study further confirmed that a high-fat meal significantly altered the PK profile of cefdinir dispersible tablets in healthy Chinese subjects, which aligns with findings from previous studies.\u003c/p\u003e \u003cp\u003eAccording to these guidelines, the cleaning period generally more than seven times the half-life of the test doses(Xu et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2023\u003c/span\u003e; Zhang et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). According to the instructions, the T\u003csub\u003e1/2\u003c/sub\u003e of cefdinir is about 1.6 to 1.8h, so it is reasonable for this study to set the cleaning cycle (dosing interval) to 7 days, which is more than 7 times the T\u003csub\u003e1/2\u003c/sub\u003e.\u003c/p\u003e \u003cp\u003eIntrasubject variability of preparations for PK parameters (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) exceeding 30% are considered highly variable drugs(Z. Li et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Su et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Based on the Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, the CV (%) of cefdinir preparations for PK parameters were less than 30%, indicating that neither cefdinir dispersible tablets nor cefdinir capsules was a highly variable drug.\u003c/p\u003e \u003cp\u003eThe BE analysis revealed that the 90% CIs of the GMR (T/R) of both formulations were in the range of 80\u0026ndash;125% after logarithmic conversion, suggesting that the test and reference cefdinir tablets were bioequivalent. Moreover, the safety evaluation revealed that cefdinir dispersible tablets were safe and well tolerated. A total of 18 AEs were reported, all of which were grade I in severity, and there were no serious AEs or deaths. In summary, the text and reference formulations were bioequivalent, with no observable safety differences in the fasting/fed state.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results of the present study revealed that the test cefdinir dispersible tablets were bioequivalent to the reference formulation in healthy Chinese subjects under both fasting and fed states, and the safety profiles of the test and reference formulations were similar. The absorption of both the test and reference formulations was affected by the ingestion of food. On the basis of these PK features, the cefdinir dispersal tablets, produced by Guangdong BoZhou Pharmaceutical Co., Ltd., is expected to be an alternative option to the reference tablet.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eThe authors are grateful to the volunteers in this study and the Phase I Clinical Trial Center team members of Panyu Central Hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors contribution\u0026nbsp;\u003c/strong\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Z.X. and J.S.. The original draft of the manuscript was written by N.M. and B.W., with additional review and editing by X.L.. The inspection of sample testing process, data, report and calculation process was conducted by D.Z. and J.L.. All authors commented on previous versions of the manuscript and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e This work was supported by Guangdong Basic and Applied Basic Research Fund Enterprise Joint Fund [grant numbers 2023A1515220024], Medical Research Foundation of Guangdong Province [grant numbers 2024070], Guangdong Hospital Pharmaceutical Research Fund project funding [grant numbers 2024A31], the Research Funds from Guangzhou Panyu Central Hospital [grant numbers PY-2023-007, PY-2023-010, PY-2023-026].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e Data are availability from corresponding author upon reasonable request but remain subject to all applicable legal requirements to protect the confdentiality of the study participants\u0026rsquo; personal information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e This clinical trial was registered in the China Drug Trials Registry (http://www.chinadrugtrials.org.cn; registration number: CTR20210441; registration date: March 11, 2021). It was approved by the Ethics Committee of Panyu Central Hospital (Clinical Research Ethics Committee approval number: PYZXYYEC【2020-029】) and was conducted independently at the Phase I Clinical Trial Research Center of Panyu Central Hospital from March 15, 2021 to April 12, 2021. This study complied with the requirements of the Declaration of Helsinki (1989), Guidelines of Good Clinical Practice, and other related guiding principles.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from all individual participants included in the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e No identifying details in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAdler M, McDonald PJ, Trostmann U, Keyserling C, Tack K (2000) Cefdinir vs. amoxicillin/clavulanic acid in the treatment of suppurative acute otitis media in children. 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Adverse Drug React J, (03), 152\u0026ndash;158\u003c/span\u003e\u003c/li\u003e\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":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"bioequivalence, healthy Chinese volunteers, cefdinir dispersible tablets, pharmacokinetics, safety","lastPublishedDoi":"10.21203/rs.3.rs-4954921/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4954921/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCefdinir is a broad-spectrum antibiotic with good antibacterial activity against gram-positive and gram-negative bacteria, and can be used for the treatment of various sensitive bacterial infections, such as community-acquired pneumonia, urinary tract infection and gonorrhea. Herein, a single-centred, randomized, open, single-dose, two-preparation, two-cycle, two-sequence, double-crossover trial with a 7-day washout was conducted to investigate the pharmacokinetics, bioequivalence and safety of cefdinir dispersible tablets and the reference formulation of cefdinir capsules in healthy Chinese volunteers. Fifty-six healthy subjects were recruited and randomly assigned to the fasting and fed groups. After a single oral dose of the test or reference formulation (0.1 g), the cefdinir concentrations in the plasma were determined via HPLC-MS/MS, and pharmacokinetic parameters were obtained from the concentration‒time profiles. Overall, 24 and 31 individuals completed the evaluation under fasting and fed conditions, respectively. The mean concentration‒time profiles for both formulations were similar, and the C\u003csub\u003emax\u003c/sub\u003e, AUC\u003csub\u003e0\u0026ndash;t\u003c/sub\u003e and AUC\u003csub\u003e0\u0026ndash;\u0026infin;\u003c/sub\u003e values were entirely within the bioequivalence range of 80.00\u0026ndash;125.00%. 3 subjects reported 5 AEs and 8 subjects experienced 13 AEs in the fasting and fed group, respectively, but no participants withdrew from the trial because of AEs. All adverse reactions were grade I in severity, and no serious AEs or deaths occurred. The results demonstrated that these formulations were bioequivalent in healthy Chinese subjects under fasting and fed conditions, supporting the further clinical development of cefdinir dispersible tablets. This trial was registered in the China Drug Trials Registry (registration number: CTR20210441; registration date: March 11, 2021).\u003c/p\u003e","manuscriptTitle":"Bioequivalence of Cefdinir Dispersible Tablets in healthy Chinese subjects under fasting and fed conditions: A Single-Centred, Randomized, Open, Single-Dose, Two-Preparation, Two-Cycle, Two-Sequence, Double-Crossover Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-15 09:13:29","doi":"10.21203/rs.3.rs-4954921/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2024-09-20T00:39:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214797299391554640336899560396610778867","date":"2024-09-09T08:03:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-03T10:06:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-22T11:01:47+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-22T11:01:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Naunyn-Schmiedeberg's Archives of Pharmacology","date":"2024-08-22T04:02:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"naunyn-schmiedebergs-archives-of-pharmacology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nsap","sideBox":"Learn more about [Naunyn-Schmiedeberg's Archives of Pharmacology](https://www.springer.com/journal/210)","snPcode":"210","submissionUrl":"https://submission.nature.com/new-submission/210/3","title":"Naunyn-Schmiedeberg's Archives of Pharmacology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"02652077-9a11-46ae-9509-56cd907698a8","owner":[],"postedDate":"October 15th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-23T16:07:18+00:00","versionOfRecord":{"articleIdentity":"rs-4954921","link":"https://doi.org/10.1007/s00210-024-03701-8","journal":{"identity":"naunyn-schmiedebergs-archives-of-pharmacology","isVorOnly":false,"title":"Naunyn-Schmiedeberg's Archives of Pharmacology"},"publishedOn":"2024-12-16 15:57:34","publishedOnDateReadable":"December 16th, 2024"},"versionCreatedAt":"2024-10-15 09:13:29","video":"","vorDoi":"10.1007/s00210-024-03701-8","vorDoiUrl":"https://doi.org/10.1007/s00210-024-03701-8","workflowStages":[]},"version":"v1","identity":"rs-4954921","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4954921","identity":"rs-4954921","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}