Single-Dose Bioequivalence Study of Elagolix Tablets 200 mg (Test Product) and Elagolix Tablets 200 mg (Reference Product) in Healthy Non-Pregnant, Non-Lactating Premenopausal Female Subjects Under Fasting Conditions

This study was supported by Sun Pharma Laboratories Limited.

Of the 60 subjects enrolled in the study, 59 subjects completed all study periods, while one subject (Subject No. 01) was withdrawn early (Figure  2 ). Pharmacokinetic analyses included data from all 60 subjects. The mean (± SD) age was 31 ± 5 years in both the dosed and completed groups. The mean body weight was 57.1 ± 7.8 kg among dosed subjects and 57.1 ± 7.9 kg among those who completed the study. The mean height was 151.7 ± 3.8 and 151.6 ± 3.8 cm, respectively, while the mean BMI was 24.8 ± 3.3 kg/m 2 in both groups. Study subject disposition flow diagram. A single 200 mg dose of Elagolix tablet was administered under fasting conditions. The pharmacokinetic (PK) parameters, including C max , AUC 0‐t , and AUC 0‐∞ , were assessed using geometric least square means (GLSMs). The results demonstrated comparable values between the test and reference formulations, as summarized in Table  1 . For both products, peak concentrations (C max ) were observed at approximately the same time (T max ), followed by a gradual decline over the 24‐h sampling period (Figure 3 ). Pharmacokinetic Parameters After a Single Oral Dose of 200 mg Elagolix AUC 0‐∞ , area under the concentration–time curve from 0 to infinity; AUC 0‐t , area under the concentration–time curve from 0 to time t; CI, confidence interval; C max , maximum concentration; CV, coefficient of variation; T 1/2 , half‐life; T max , time to maximum concentration. * Mean. # Median. Mean plasma concentration–time curves for test and reference products a) Linear‐scale b) Semi‐logarithmic scale. The mean plasma concentration–time profiles of Elagolix for both the test (T1, T2) and reference (R1, R2) formulations were comparable. Plasma concentrations increased rapidly after dosing, reaching peak levels (C max ) at approximately 1‐2 h (T max ), followed by a gradual decline. Concentrations approached baseline by 12‐15 h, with negligible levels observed at 24 h. The overall absorption and elimination patterns were similar across formulations, with only minor differences in peak concentrations. The geometric least squares mean ratio for the log‐transformed C max met the 95% upper confidence bound criteria, indicating comparable peak plasma concentrations. Similarly, the ratios of log‐transformed pharmacokinetic parameters AUC 0‐t and AUC 0‐∞ fell within the standard 90% confidence interval range of 80.00% to 125.00%, which met the requirements of bioequivalence. The intra‐subject coefficient of variation (CV%) for C max confirmed the highly variable nature of Elagolix (Table  1 ). A total of five adverse events (AEs) were observed in five subjects throughout the study, all of which were mild in severity. Two AEs (headache and vomiting) were deemed possibly related to the test product, while two AEs of dizziness were possibly associated with the reference product. Decreased hemoglobin in one patient was considered unlikely to be related to the reference product. All subjects were monitored until the resolution of their respective AEs. No serious adverse events (SAEs) were reported during the study.

This was an open‐label, randomized, four‐period, two‐treatment, two‐sequence, fully replicated, crossover, balanced, single‐dose bioequivalence study conducted in healthy, non‐pregnant, non‐lactating premenopausal female subjects under fasting conditions. The study was approved by the Institutional Ethics Committee of Sehgal Nursing Home (IEC‐SNH), Delhi (ECR/1148 /Inst/DL/2018/RR‐21) on May 12, 2022. A no objection certificate (NOC) for the conduct of the study was obtained from the Drugs Controller General of India (DCGI) before study initiation. The study was conducted in accordance with the principles of the Declaration of Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, and applicable national regulatory requirements. Written informed consent was obtained from all subjects (or their guardian/s) prior to initiation of the study. The bioequivalence (BE) study was conducted using the 200‐mg strength, which represents the highest approved strength of the formulation. According to regulatory guidance (ICH M13A Bioequivalence for Immediate‐Release Solid Oral Dosage Forms), when multiple strengths are developed, the strength selected for BE evaluation should consider dose proportionality and solubility characteristics, and generally the highest marketed strength may be administered as a single unit. As the formulation demonstrates dose proportional pharmacokinetics and the highest approved strength is 200 mg, BE evaluation at this strength was considered appropriate. Healthy, non‐pregnant, non‐lactating premenopausal females aged 18‐40 years with a body mass index (BMI) between 18.5 and 30.0 kg/m 2 were considered eligible. Subjects with any clinically significant medical conditions, history of drug or alcohol abuse, pregnancy, lactation, or those who failed laboratory safety assessments were excluded. Subjects on any medication or supplements, or with a history of hypersensitivity to Elagolix or similar drugs, were also excluded. The test product was Elagolix (Egolix ™ ) Tablets 200 mg manufactured by Sun Pharmaceutical Industries Limited, India, and the reference product was Elagolix Tablets 200 mg (OrilissaTM product) manufactured by AbbVie Inc., North Chicago, IL. The study was conducted at Cliantha Research Limited, India. Eligible subjects were randomly divided into two groups (Group I and Group II), with dosing conducted in four periods. In Group I, the intervals between doses (Period 1 to 2, Period 2 to 3, and Period 3 to 4) were 4, 4, and 6 days, respectively. In Group II, the intervals between doses were consistently 4 days. A single oral dose of 200 mg of the test or reference product was administered in a sitting posture after an overnight fast of at least 10 h. Each dose was followed by 240 mL of ambient‐temperature water under supervision. Blood samples (2 mL) were collected pre‐dose (0.000 h) and post‐dose at 0.167, 0.250, 0.333, 0.500, 0.750, 1.000, 1.250, 1.500, 1.750, 2.000, 2.500, 3.000, 4.000, 5.000, 6.000, 8.000, 10.000, 12.000, 16.000, and 24.000 h (Figure  1 ) Samples were shipped to the bioanalytical facility for analysis. Flowchart of study design and procedure. Elagolix concentrations in plasma were quantified using a validated ultra high‐performance liquid chromatography‐tandem mass spectrometric (UHPLC‐MS/MS) method. Elagolix‐13C‐D3 was used as the internal standard, and sample preparation was performed using the solid phase extraction technique. The analytical range for Elagolix in plasma was 4.03 to 2386.11 ng/mL. The analytical method was developed and validated at the Department of Clinical Pharmacology and Pharmacokinetics, Sun Pharmaceutical Industries Ltd., Gurugram, India. Parameters such as precision, accuracy, linearity, and stability were validated according to regulatory guidelines. Pharmacokinetic parameters were estimated using plasma concentration–time data, including AUC 0‐t , AUC 0‐∞ , C max , T max , K el , t½, and AUC% Extrapolation. The primary endpoints included AUC 0‐t , AUC 0‐∞ , and C max , while the secondary endpoints included T max , K el , t½, and AUC% Extrapolation. The bioequivalence of the test and reference products was assessed by calculating the log‐transformed pharmacokinetic parameters (C max , AUC 0‐t , and AUC 0‐∞ ). As per regulatory guidelines, the bioequivalence range was set between 80.00% and 125.00% for the 90% confidence interval of C max , AUC 0‐t , and AUC 0‐∞ or 95% upper confidence if within reference variability >30%. Elagolix is a highly variable drug, with a coefficient of variation (CV%) greater than 30%, and therefore requires a replicate study design. Log transformation was applied to ensure the normality of the data for statistical analysis, and the derived confidence intervals were compared against the regulatory limits to establish bioequivalence between the test and reference products. Sample size estimation was performed considering pharmacokinetic variability of Elagolix (Sun data on file). Assuming a Test/Reference geometric mean ratio (GMR) within 90%‐110% and an intra‐subject coefficient of variation (CV) of approximately 34%, a total of 100 observations (equivalent to 50 subjects in a fully replicate design) were considered to provide an estimated statistical power of about 80% to demonstrate bioequivalence under standard assumptions. With an assumed dropout rate of 20%, a total of 60 subjects were enrolled to account for dropouts. The PK parameters for Elagolix plasma concentration was calculated using standard non‐compartmental analysis using Phoenix WinNonlin Software Version 8.1 (Certara, USA). The individual within‐subject standard deviations (SWR) of the pharmacokinetic parameters AUC 0‐t , AUC 0‐∞ , and C max of the reference formulation of Elagolix were used to assess bioequivalence by applying average bioequivalence (ABE) or reference‐scaled average bioequivalence (RSABE) methods. The variability of the reference product was calculated using an ANOVA procedure. Log‐transformed pharmacokinetic parameters (C max , AUC 0‐t , and AUC 0‐∞ ) were analyzed using an ANOVA model on the individual differences of the reference product for each subject. The analysis employed a Type III sum of squares, with sequence and group considered as fixed effects. This statistical approach ensured a thorough evaluation of the reference product's variability, following the methodology outlined in the Draft Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA, August 2021. The within‐subject variability observed for reference product was greater than 30% (within‐subject standard deviation for reference product ≥0.294) for log‐transformed pharmacokinetic parameter C max ,, and the within‐subject variability observed for reference product was less than 30% (within‐subject standard deviation for reference product <0.294) for log‐transformed pharmacokinetic parameters AUC 0‐t and AUC 0‐∞ . Therefore, For Elagolix, RSABE approach was used for C max , and ABE approach was used for AUC 0‐t and AUC 0‐∞ . Bioequivalence calculations was performed using SAS statistical software (Version: 9.4 or higher; SAS Institute Inc., USA). Safety assessments included physical and gynecological examinations, chest x‐ray (within 6 months), ECG, and baseline lab tests (hematology, biochemistry, urinalysis, immunology, cholesterol, and serum β‐HCG pregnancy tests). Vital signs (sitting blood pressure, radial pulse, and body temperature) were recorded at check‐in, pre‐dosing (within 120 min), 2.0 h (±40 min) post‐dose, and at 6.0 and 10.0 h (±40 min) post‐dose to ensure participant safety throughout the study. Subjects were instructed to self‐report any adverse events. Additionally, adverse events were actively assessed by trained study personnel using non‐leading, structured inquiry during clinical examinations, vital sign assessments, and at approximately 16.0‐ and 24.0‐h post‐dose in each study period.

Pharmacokinetic evaluation confirmed that a single 200 mg oral dose of Elagolix (Egolix ™ , Sun Pharmaceutical Industries Limited, India) was bioequivalent to the global reference product. The test formulation was well tolerated, with no clinically significant adverse effects reported.

This study represents the first direct comparison of the bioequivalence and PK profiles of a single 200 mg Elagolix tablet with the global reference product under fasting conditions in healthy premenopausal women. The selection of key PK parameters—C max , AUC 0‐t , and AUC 0‐∞ —was deliberate, as these metrics are standard indicators for assessing the rate and extent of drug absorption, respectively. 15 According to the US FDA's guidelines for bioequivalence studies, for a test product to be bioequivalent to a reference, the 95% upper confidence bound for the log‐transformed test/reference ratio of PK parameters must be ≤0, and the GMR for C max , AUC 0‐t , and AUC 0‐∞ must fall within the range of 80.00% to 125.00%. This study met both criteria, with the GMRs for all PK parameters within the acceptable range and the confidence bounds satisfying FDA guidelines. These results confirm the bioequivalence of the test product to the reference, ensuring comparable systemic exposure. 15 In this study, following a single 200 mg oral dose of Elagolix under fasting conditions, C max was reached within 1.2 h. This finding is consistent with the study by Ng et al (2017), which reported peak plasma concentrations of Elagolix within 1.0 to 1.5 h and a half‐life ranging from 4 to 6 h. A washout period of 4 days was maintained between all subsequent periods, except on one occasion where a 6‐day washout was implemented due to logistical reasons. Given the terminal elimination half‐life of 4‐6 h, this additional 2‐day washout in a single period is not expected to influence the pharmacokinetic outcomes, as it exceeds the time required for complete drug elimination. Minor variations in pharmacokinetic parameters, including concentration and half‐life, observed across studies may be attributed to differences in study design, dosing regimens, population demographics, or analytical methodologies. Nonetheless, our findings align closely with existing literature, underscoring the reproducibility of Elagolix's absorption and elimination profiles across diverse populations. 16 , 17 In a Phase III, randomized, multicentric, double‐blind, double‐dummy, parallel‐group, active‐controlled, comparative, non‐inferiority study (CTRI/2023/01/049292), Elagolix 150 mg (Egolix ™ 150, manufactured by Sun Pharma) was compared with Dienogest 2 mg for reducing pain associated with endometriosis. The primary endpoint, the reduction in NRS score from baseline to Day 85 in the test arm, was non‐inferior to the comparator arm (Test: −2.43 ±1.28; Comparator: −2.47 ±1.26; treatment difference [T − C] [95% CI]: 0.04 [−0.3, 0.37]) as the upper 95% CI was below the pre‐defined margin of 1.5. Similar findings were observed at Day 169, with the test arm being non‐inferior to the comparator (Test: −4.33 ±1.46; Comparator: −4.37 ±1.28; T − C [95% CI]: 0.04 [−0.32, 0.4]). Reductions in dysmenorrhea (DYS), NMPP scores, the proportion of patients requiring rescue medication, and responder rates on the PGI‐C scale were also comparable between groups. Notably, the incidence of treatment‐emergent adverse events was similar across both treatment arms, with no SAEs reported. These findings strengthen the role of Elagolix in endometriosis management. In terms of safety, the incidence of AEs in our study was low, with all reported AEs being mild in severity and resolving without intervention. The most commonly reported AEs, such as headaches and hot flushes, are typically mild to moderate in intensity and self‐limiting in nature. 12 , 16 , 18 Thus, the favorable pharmacokinetic properties and safety profile position Elagolix as a potentially pivotal treatment for Indian women who have endometriosis. This research has the potential to support the clinical adoption of Elagolix in India, offering a targeted and effective treatment option. Ultimately, the introduction of Elagolix may revolutionize endometriosis management in India, addressing the long‐standing unmet needs of patients struggling with this condition. There are a few limitations, including the exclusion of women with comorbid conditions or ongoing treatments limit the generalizability of the findings. Additionally, the study only assessed single‐dose administration and did not evaluate steady‐state pharmacokinetics or long‐term safety, which are critical for chronic conditions like endometriosis. Further research should evaluate Elagolix under chronic dosing to reflect real‐world use, including diverse populations, and long‐term safety.

The authors are full‐time employees of Sun Pharma.

Endometriosis is a chronic inflammatory condition affecting approximately 10% of women of reproductive age, impacting around 247 million women worldwide and 42 million in India. It is a leading cause of significant pain, infertility, and a reduced quality of life. 1 The prevalence of endometriosis further rises to 70% in women with chronic pelvic pain and up to 50% in those with infertility. In the most extensive cohort study conducted in India, deep infiltrating endometriosis (DIE) was identified in 24% of women, with 23% reporting dyspareunia. Beyond its physical burden, endometriosis presents substantial social, public health, and economic challenges, often leading to debilitating pain during menstruation, sexual activity, bowel movements, or urination. It is also linked to symptoms such as chronic pelvic pain, bloating, nausea, fatigue, and mental health issues, including anxiety and depression. 2 Moreover, studies have suggested an association between endometriosis and an increased risk of ovarian cancer. Given these widespread implications, addressing this condition is essential for improving reproductive health, overall well‐being, and quality of life. 3 One of the key challenges in managing endometriosis is delayed diagnosis, which prolongs suffering and can contribute to infertility. Several risk factors have been identified, including early menarche (before 11 years), short menstrual cycles (fewer than 27 days), heavy menstrual bleeding, and nulliparity. These factors highlight the strong hormonal influences underlying the disease, particularly the imbalance of high estrogen and low progesterone levels. 3 A particularly distressing symptom of endometriosis is dyspareunia, which affects nearly half of women with the condition and significantly impairs their quality of life. Despite its high prevalence, the mechanisms underlying deep dyspareunia in endometriosis remain poorly understood. Research has suggested that deep endometriotic nodules, particularly those in the rectovaginal septum, uterosacral ligaments, and cul‐de‐sac, may contribute to this pain. 4 Additionally, an overexpression of nerve growth factor (NGF) has been proposed as a potential mechanism. 5 However, the response to medical treatment varies widely among patients, with many showing inadequate relief from standard hormonal therapies. This inconsistent treatment response may be attributed to a limited understanding of the complex pain mechanisms involved in endometriosis, particularly in cases of deep dyspareunia. 6 Current treatment strategies for endometriosis primarily involve progestin‐only therapies and combined oral contraceptives (COCs), which serve as the first‐line pharmacological options. 7 However, up to one third of women with symptomatic endometriosis do not respond to progestins, possibly due to progesterone resistance. 8 This resistance is linked to altered progesterone receptor (PGR) expression, particularly the loss or reduction of progesterone receptor‐B (PR‐B) in endometriotic lesions and eutopic endometria. 9 To address the limitations of existing treatments, Elagolix, an orally active, short‐acting nonpeptide gonadotropin‐releasing hormone (GnRH) antagonist, was developed. 9 , 10 Unlike long‐acting GnRH agonists, which cause an initial 1‐2 week “flare‐up” due to receptor downregulation, Elagolix functions through competitive antagonism of GnRH receptors, providing a rapid and reversible onset and offset. This mechanism allows for more precise modulation of the hypothalamic–pituitary–gonadal axis, offering greater flexibility and control in managing endometriosis. 11 Landmark trials, Elaris EM‐I and Elaris EM‐II, demonstrated the efficacy of Elagolix in treating moderate to severe endometriosis‐related pain, with the higher dose of 200 mg achieving superior responder rates for both menstrual and non‐menstrual pelvic pain (NMPP) at 6 months. 12 Recognizing its benefits, the 2022 European Society of Human Reproduction and Embryology (ESHRE) guidelines strongly recommend GnRH antagonists for reducing endometriosis‐associated pain, though specific guidance on dosage and treatment duration remains limited. 13 Similarly, the American Academy of Family Physicians (AAFP) endorses Elagolix 200 mg for women with endometriosis who also experience dyspareunia. 14 Elagolix has been approved by major regulatory agencies, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), as well as in Israel. In 2024, Elagolix became available in India following a Phase III clinical trial conducted among Indian patients. This study was planned to assess the pharmacokinetics and safety of Elagolix. We aimed to compare the highest strength of Elagolix (Egolix ™ 200 mg) with the reference product as per the guidance on bioequivalence (BE) study designs by drug regulators.