Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed-Dose Combination Product: Phase 1 Results in Healthy Pre- and Postmenopausal Women

Fixed-dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin-releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add-back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300-mg capsule relative to the commercially available elagolix 300-mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300-mg tablet coadministered with E2/NETA 1-mg/0.5-mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300-mg capsule was bioequivalent to the reference elagolix 300-mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5-mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high-fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration-time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline-adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule. Endometriosis and uterine fibroids are hormone-dependent conditions.1, 2 Elagolix is a novel oral gonadotropin-releasing hormone (GnRH) receptor antagonist. The clinical pharmacokinetics (PK), PK/pharmacodynamics, and drug-drug interaction of elagolix have been well-characterized in several studies.3-7 Elagolix inhibits endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Administration of elagolix results in dose-dependent suppression of luteinizing hormone and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones estradiol (E2) and progesterone.8 Dose-dependent suppression of E2 was previously demonstrated, with maximum suppression achieved with elagolix 200 mg twice daily. Dose-dependent suppression of FSH and luteinizing hormone was also observed, with maximal or near-maximal suppression achieved at 300 mg twice daily and 200 mg twice daily, respectively.8 The hypoestrogenic effects that result from the decreased hormone levels may lead to decreased bone mineral density and vasomotor symptoms. To minimize these effects, hormonal “add-back” therapy can be used to replace the reduced levels of endogenous hormones.9, 10 The investigational drug product that was studied in the elagolix uterine fibroid Phase 3 trials was elagolix 300-mg twice daily immediate-release tablets coadministered with add-back therapy of the estradiol/norethindrone acetate (E2/NETA) 1-mg/0.5-mg once-daily tablet.9 To improve patient compliance with the treatment regimen and for greater convenience, a fixed-dose combination (FDC) capsule consisting of elagolix/E2/NETA 300/1/0.5 mg for the morning dose, and an elagolix 300-mg capsule for the evening dose was developed as the commercially intended product. The 2 formulations exhibited dissimilarity in vitro based on dissolution profiles, indicating potentially different release characteristics in vivo. Two bioequivalence studies including the food effect were conducted to evaluate and bridge the elagolix capsule and elagolix/E2/NETA FDC capsules to the Phase 3 tablets. In Study 1, the bioequivalence of the elagolix 300-mg capsule relative to that of the 300-mg elagolix tablet was assessed in healthy premenopausal women. In Study 2, the bioequivalence of the elagolix/E2/NETA FDC capsule compared to the 300-mg elagolix tablet coadministered with the E2/NETA tablet was assessed in healthy postmenopausal women. The effect of a high-fat meal on the elagolix capsule and on the elagolix/E2/NETA FDC capsule was also evaluated.

The studies were conducted in accordance with the protocols and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. Quorum Review Institutional Review Board (IRB) (Seattle, WA), Aspire IRB (Santee, CA), and Salus IRB (Austin, TX) reviewed and approved the study protocols and informed consent forms. The study was conducted at the AbbVie Clinical Pharmacology Research Unit (Grayslake, IL), Anaheim Clinical Trials, LLC (Anaheim, CA), PPD Development LP (Austin, TX), and WCCT Global (Cypress, CA). Written informed consent was obtained before each subject's participation in the studies. Study Subjects Healthy premenopausal women between the ages of 18 and 49 inclusive and regular menstrual cycles of 24-38 days were eligible for Study 1. Subjects in Study 2 were healthy postmenopausal women aged 55-70 years with no menses for 12 or more months without an alternative medical cause (with the exception of a hysterectomy), or 55 years or younger with no menses for 12 or more months without an alternative medical cause and FSH concentration greater than 40 IU/L. Body mass index of 18.0 or greater to 29.9 kg/m2 or less was required in both studies. Health status was assessed by review of medical history, physical examination, vital sign measurement, 12-lead electrocardiogram (ECG), and laboratory tests. Study Design The studies were Phase 1, single dose, open-label, 4-sequence, 2- or 3-period, randomized, crossover design (Table S1) conducted at a single center in premenopausal women (Study 1) and at 4 centers in postmenopausal women (Study 2). In Study 1, the bioavailability of the elagolix 300-mg capsule (test) was assessed relative to the elagolix 300-mg tablet (reference), and the effect of a high-fat meal on the elagolix capsule was evaluated. A washout interval of 5 days separated the doses of the study periods. In Study 2, the elagolix/E2/NETA (300-mg/1-mg/0.5-mg) FDC capsule was the test treatment relative to the reference treatment of the elagolix 300-mg tablet coadministered with the E2/NETA 1-mg/0.5-mg tablet. The effect of food on the elagolix/E2/NETA FDC capsule was evaluated. A washout interval of 4 days separated the doses of the study periods. The full description of the components of the high-fat breakfast of Studies 1 and 2 is provided in the Supplemental Information. Pharmacokinetic Assessments and Bioanalysis Estradiol (E2) and estrone (E1) are the 2 predominant estrogens in circulation, with multiple functions throughout the body. E2 and E1 are in equilibrium by converting into each other via action of 17β-hydroxysteroid dehydrogenases.11 The literature indicates that E1 can exert clinical effects independent of E2.12 Thus, to better understand the overall estrogen levels and E2:E1 in ratios in circulation, both E2 and E1 levels are generally measured together. This approach has been widely accepted in clinical development of hormone-based therapy.12-14 Therefore, in addition to measuring elagolix, E2, and norethindrone concentrations, E1 concentrations (as unconjugated E1 and total E1) are also measured in these bioequivalence (BE) studies. - Elagolix: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours - Norethindrone: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 60, and 72 hours - Total E1: –1.0, –0.5, 0, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 30, 36, 48, 60, and 72 hours - Unconjugated E2 and unconjugated E1: –0.5, 0, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, and 60 hours Blood samples for the assay of elagolix, norethindrone, unconjugated E2, and unconjugated E1 and/or total E1 were collected in evacuated dipotassium ethylenediaminetetraacetic acid collection tubes. The blood samples were centrifuged to separate the plasma and were placed in a −20°C freezer until analysis. The Bioanalysis Department at AbbVie Inc. developed and validated 2 high-performance liquid chromatography (HPLC)–tandem mass spectrometry methods to analyze elagolix and norethindrone plasma concentrations. Syneos Health developed and validated 2 HPLC–mass spectrometry methods to analyze unconjugated E2, unconjugated E1, and total E1 plasma concentrations, with unconjugated E1 and E2 as Method 1 and total E1 as Method 2. Salt-assisted liquid-liquid extraction was used to isolate elagolix from 0.050 mL of human plasma. Elagolix and its stable isotope-labeled internal standard, elagolix-d5, were subjected to reverse-phase HPLC analysis on an Agilent Zorbax SB-C18 column (2.1 × 50 mm, 5 µm) with an isocratic elution at 0.600 mL/min using a mobile phase of 50/50/0.05/0.25 (v/v/v/v) acetonitrile/water/acetic acid/2 M ammonium acetate in water. A Sciex API 5500 triple quadrupole mass spectrometer with an electrospray ionization (ESI) inlet in the positive multiple reaction monitoring (MRM) mode was used for detection. The elagolix peak area was measured against the peak area of the elagolix-d5 internal standard. The precursor-to-product ion transitions were m/z 632 to 529 for elagolix and m/z 637 to 534 for elagolix-d5. The nominal range of quantitation used during the studies was 0.100-2500 ng/mL for elagolix. Liquid-liquid extraction was used to isolate norethindrone from 0.200 mL of human plasma. Norethindrone and its stable isotope-labeled internal standard, norethindrone-d6, were subjected to reverse-phase HPLC analysis on an Agilent Zorbax SB-C18 column (2.1 × 50 mm, 3.5 µm) with an isocratic elution at 0.800 mL/min using a mobile phase of 40/60 (v/v) acetonitrile/(water with 0.2% formic acid and 2 mM ammonium formate). A Sciex API 5500 triple quadrupole mass spectrometer with an ESI inlet in the positive MRM mode was used for detection. The norethindrone peak area was measured against the peak area of the norethindrone-d6 internal standard. The precursor-to-product ion transitions were m/z 299 to 109 for norethindrone and m/z 305 to 113 for norethindrone-d6. The nominal range of quantitation used during the study was 0.101-58.3 ng/mL for norethindrone. Solid-phase extraction and derivatization were used to isolate unconjugated E1 and unconjugated from 0.600 mL of human plasma. Unconjugated E1 and unconjugated E2 and their respective stable isotope-labeled internal standards, estrone-d4, and estradiol-d5, were subjected to reverse-phase HPLC analysis on an ACE Excel 2 C18 column (3.0 × 75 mm, 2 µm) with an isocratic elution at 0.500 mL/min using a mobile phase a solution of water with 0.2% acetic acid and a mobile phase b solution of methanol with 0.2% acetic acid. A Sciex API 5000 triple quadrupole mass spectrometer with an ESI inlet in the positive MRM mode was used for detection. The unconjugated E1 peak area was measured against the peak area of the estrone-d4 internal standard. The precursor-to-product ion transitions were m/z 504 to 171 for unconjugated E1 and m/z 508 to 171 for estrone-d4. The unconjugated E2 peak area was measured against the peak area of the estradiol-d5 internal standard. The precursor-to-product ion transitions were m/z 506 to 171 for unconjugated E2 and m/z 511 to 171 for estradiol-d5. The nominal range of quantitation used during the study was 5.0-1000 pg/mL for unconjugated E1 and 2.5-250 pg/mL for unconjugated E2. Liquid-liquid extraction and derivatization were used to isolate total E1 from 0.200 mL of human plasma. Total E1 and its stable isotope-labeled internal standard, estrone-d4, were subjected to reverse-phase HPLC analysis on an ACE C18-HL column (4.6 × 50 mm, 3 µm) with an isocratic elution at 1.00 mL/min using a mobile phase a solution of water/methanol with acetic acid and a mobile phase b solution of methanol. A Sciex API 5000 triple quadrupole mass spectrometer with ESI inlet in the positive MRM mode was used for detection. The total E1 peak area was measured against the peak area of the estrone-d4 internal standard. The precursor-to-product ion transitions were m/z 504 to 171 for total E1 and m/z 508 to 171 for estrone-d4. The nominal range of quantitation used during the study was 10.0-20 000 pg/mL for total E1. Human plasma calibration standards were used to quantitate human quality control samples and unknown specimens. The samples were analyzed by subject. Concentrations above the limits were determined by sufficiently diluting the samples into the respective nominal concentration ranges and then applying the factor used to perform the dilution. Any samples that were quantified below the lowest standard were reported as 0. The accuracy (expressed as percentage bias) for elagolix, norethindrone, unconjugated E1, unconjugated E2, and total E1 ranged from −4.5% to 0%, −0.4% to 2.5%, −3.1% to 17.1%, −0.2% to 11.0%, and −5.8% to 7.5%, respectively. The elagolix statistics listed above encompass the performance of the assay from both studies. Sample Size Calculation The study populations of the 2 studies were different considering the impact of E2/NETA tablet on premenopausal women. The sample size of Study 1 was calculated mainly on the basis of within-subject variability of natural logarithm of maximum concentration (Ln[Cmax]) of elagolix from a previous bioavailability study assuming point estimates of the test/reference geometric mean ratios ranged from 0.92 to 1.08. The sample size of Study 2 was calculated mainly on the basis of within-subject variability of Ln(Cmax) of baseline-adjusted total E1 from the previous bioavailability study, assuming point estimates of the test/reference geometric mean ratio ranged from 1.00 to 1.16. Statistical Analysis and BE Assessment The PK data were analyzed and compared between the test and reference drug groups. A linear mixed effects analysis was performed for Tmax, β, and the natural logarithms of Cmax, AUCt and AUCinf with the data from the first two periods. To assess the BE between the formulations under fasting conditions, a point estimate of the bioavailability of the test formulation relative to the reference formulation was provided by taking the antilogarithm of the estimate of the difference of logarithm means. The bioavailability of test relative to that of the reference was assessed by a 2 one-sided tests procedure via 90% confidence intervals (CIs) for the difference of the least-squares means obtained from the analyses of the natural logarithms of Cmax, AUCt and AUCinf. To assess the effect of food on the PK of the elagolix test formulation for Cmax and AUC, the ratio of the central value for the test formulation under fed conditions relative to that under fasting conditions was estimated, and the corresponding 90% CI for the ratio of the central values was constructed. The formulations were considered to be bioequivalent if the 90% CI of the geometric mean ratio (test/reference) Cmax and AUCinf were within the range of 0.80-1.25. Safety Monitoring Safety was assessed through adverse event monitoring, vital sign measurements, physical examinations, ECGs, and clinical laboratory testing, which included hematology, chemistry, and urinalysis. Adverse events of special interest (hepatic transaminase elevations and mood/depression-related events), if any, were to be further evaluated using questionnaires.

Subject Disposition A total of 57 premenopausal subjects were enrolled in Study 1, and 56 subjects completed dosing, with 1 subject in Sequence 2 discontinuing the study drug due to an adverse event. In Study 2, 179 postmenopausal subjects were enrolled; 12 subjects had 2 unique subject IDs, as they enrolled for the same trial at 2 study sites. Therefore 191 subject IDs were randomized to one of the 4 study sequences. Among them, 177 subjects (including 3 double-enrolled subjects) completed the study. Three subjects discontinued due to adverse events, and 4 subjects (including 2 double-enrolled subjects) withdrew their consent. A summary of demographics for both studies is shown in Table S2. Pharmacokinetics and Food-Effect Assessment for Elagolix Capsule and Elagolix/E2/NETA FDC Capsule In Study 1, the PK parameters of the elagolix for the capsule and the tablet, and for the capsule under fasting and fed conditions are summarized in Table 1. Following administration of the elagolix capsule after a high-fat breakfast, the mean Cmax and AUCinf of elagolix were 40% and 28% lower, respectively, when compared to exposures under fasting conditions, and median tmax was delayed by approximately 1.2 h (Figure 1A and Table 1). | Pharmacokinetic parameters (units) | Elagolix capsule N = 56a | Elagolix tablet N = 57 | Elagolix capsule N = 12 | Elagolix capsule N = 12 | |---|---|---|---|---| | Fasting/Fed | Fasting | Fasting | Fed | Fasting | | Cmax (ng/mL) | 1270 (553) | 1480 (667) | 828 (426) | 1380 (631) | | tmax (hour)b | 1.5 (1.0-4.0) | 1.0 (0.75-2.0) | 3.0 (2.0-6.0) | 1.8 (1.5-2.0) | | AUClast (ng•h/mL) | 3740 (1610) | 3920 (1780) | 2740 (966) | 3840 (1380) | | AUCinf (ng•h/mL) | 3740 (1610) | 3930 (1780) | 2750 (966) | 3840 (1380) | | t1/2 (hour) | 6.60 (2.12) | 6.54 (2.93) | 7.99 (1.89) | 6.59 (1.90) | - AUCinf, area under the plasma concentration-time curve from time 0 to infinity; AUClast, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration; Cmax, maximum concentration; PK, pharmacokinetic; SD, standard deviation; t1/2, terminal elimination half-life; tmax, time to maximum concentration. - a One subject discontinued before receiving the capsule. - b For tmax, median (minimum through maximum). In Study 2, the PK parameters of elagolix, norethindrone, total estrone (baseline-adjusted), and unconjugated estradiol (baseline-adjusted) following (1) a single dose of 1 elagolix/E2/NETA (300-mg/1-mg/0.5-mg) capsule under fasting conditions (Regimen A), (2) a single dose of 1 elagolix 300-mg tablet and 1 E2/NETA (1-mg/0.5-mg) tablet encapsulated under fasting conditions (Regimen B), or (3) a single dose of 1 elagolix/E2/NETA (300-mg/1-mg/0.5-mg) capsule under high-fat meal conditions (Regimen C) are summarized in Tables 2 and 3. | Pharmacokinetic parameter of each analytes (units) | Regimen A FDC capsule | Regimen B Encapsulated tablets | |---|---|---| | Elagolix | (N = 163) | (N = 165) | | Cmax (ng/mL) | 1640 (727) | 1800 (813) | | tmaxa (hour) | 1.5 (1.0-4.0) | 1.0 (0.5-24.0) | | AUCt (ng•h/mL) | 4420 (1930) | 4510 (2080) | | AUCinf (ng•h/mL) | 4420 (1930) | 4550 (2060) | | t1/2 (hour) | 3.12 (0.918) | 3.15 (0.826) | | Norethindrone | (N = 163) | (N = 165) | | Cmax (ng/mL) | 6.07 (2.13) | 5.45 (1.94) | | tmaxa (hour) | 1.0 (0.5-2.0) | 1.0 (0.5-3.0) | | AUCt (ng•h/mL) | 23.8 (11.4) | 24.7 (11.9) | | AUCinf (ng•h/mL) | 25.8 (11.6) | 26.8 (12.2) | | t1/2 (hour) | 10.5 (3.71) | 10.6 (3.57) | | Total estrone Baseline adjusted | (N = 164) | (N = 165) | | Cmax (ng/mL) | 24.4 (8.07) | 23.6 (8.06) | | tmaxa (hour) | 1.0 (0.0-4.0) | 1.0 (1.0-4.0) | | AUCt (ng•h/mL) | 182 (719) | 189 (75.8) | | AUCinf (ng•h/mL) | 186 (744) | 193 (78.8) | | t1/2 (hour) | 12.2 (3.78) | 12.6 (4.09) | | Unconjugated estradiol Baseline adjusted | (N = 163) | (N = 165) | | Cmax (pg/mL) | 57.9 (30.1) | 62.0 (36.2) | | tmaxa (hour) | 2.0 (0.0-10.0) | 2.0 (0.0-12.0) | | AUCt (pg•h/mL) | 864 (331) | 949 (379) | | AUCinf (pg•h/mL) | 982 (407)b | 1070 (488)c | | t1/2 (hour) | 17.2 (8.24)b | 17.3 (6.78)c | - AUCinf, area under the plasma concentration-time curve from time 0 to infinity; AUClast, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration; Cmax, maximum concentration; E2, estradiol; FDC, fixed-dose combination; NETA, norethindrone acetate; PK, pharmacokinetic; SD, standard deviation; t1/2, terminal elimination half-life; tmax, time to maximum concentration. - Regimen A: Single dose of 1 elagolix/E2/NETA (300-mg/1-mg/0.5-mg) capsule under fasting conditions. - Regimen B: Single dose of 1 elagolix 300-mg tablet and 1 E2/NETA (1-mg/0.5-mg) tablet encapsulated under fasting conditions. - a For tmax, median (minimum through maximum). - b N = 162. - c N = 164. | Pharmacokinetic Parameter of each analytes (units) | Regimen C FDC capsule Fed | Regimen A FDC capsule Fasting | |---|---|---| | Elagolix | (N = 12) | (N = 12) | | Cmax (ng/mL) | 1120 (324) | 1800 (632) | | tmaxa (hour) | 3.0 (2.0-6.0) | 1.5 (1.0-2.0) | | AUCt (ng•h/mL) | 3520 (997) | 4910 (1820) | | AUCinf (ng•h/mL) | 3530 (1000) | 4930 (1830) | | t1/2 (hour) | 3.16 (0.659) | 3.42 (0.851) | | Norethindrone | (N = 12) | (N = 12) | | Cmax (ng/mL) | 2.85 (0.909) | 5.79 (1.94) | | tmaxa (hour) | 4.0 (1.0-6.0) | 1.0 (1.0-1.0) | | AUCt (ng•h/mL) | 26.2 (9.91) | 21.6 (8.75) | | AUCinf (ng•h/mL) | 28.3 (10.3) | 23.5 (8.98) | | t1/2 (hour) | 10.6 (3.09) | 10.1 (3.44) | | Total estroneBaseline adjusted | (N = 12) | (N = 12) | | Cmax (ng/mL) | 14.1 (5.79) | 25.9 (10.7) | | tmaxa (hour) | 3.5 (2.0-6.0) | 1.5 (1.0-2.0) | | AUCt (ng•h/mL) | 183 (87.3) | 214 (106) | | AUCinf (ng•h/mL) | 188 (91.0) | 219 (109) | | t1/2 (hour) | 12.7 (3.33) | 13.7 (3.88) | | Unconjugated estradiol Baseline adjusted | (N = 12) | (N = 12) | | Cmax (pg/mL) | 46.3 (25.3) | 60.5 (29.1) | | tmaxa (hour) | 5.0 (2.0-6.0) | 2.0 (1.0-4.0) | | AUCt (pg•h/mL) | 995 (365) | 1020 (429) | | AUCinf (pg•h/mL) | 1190 (469) | 1160 (515) | | t1/2 (hour) | 20.6 (6.54) | 19.2 (3.54) | - AUCinf, area under the plasma concentration-time curve from time 0 to infinity; AUClast, area under the plasma concentration-time curve from time 0 to the last quantifiable concentration; Cmax, maximum concentration; E2, estradiol; FDC, fixed-dose combination; NETA, norethindrone acetate; PK, pharmacokinetic; SD, standard deviation; t1/2, terminal elimination half-life; tmax, time to maximum concentration. - Regimen A: Single dose of 1 elagolix/E2/NETA (300-mg/1-mg/0.5-mg) capsule under fasting conditions. - Regimen C: Single dose of 1 elagolix/E2/NETA (300-mg/1-mg/0.5-mg) capsule under high-fat meal conditions. - a For tmax, median (minimum through maximum). Following administration of an elagolix/E2/NETA (300-mg/1-mg/0.5-mg) FDC capsule after a high-fat breakfast, the elagolix mean Cmax and AUCinf were 38% and 28% lower, respectively, when compared to exposures under fasting conditions. NETA mean Cmax was 51% lower and AUCinf was 20% higher, while total estrone (baseline-adjusted) Cmax and AUCinf were 46% and 14% lower, respectively. Unconjugated estradiol (baseline-adjusted) mean Cmax and AUCinf were 23% lower and 3% higher, respectively. In addition, the median tmax for elagolix, norethindrone, total estrone (baseline-adjusted), and unconjugated estradiol (baseline-adjusted) were delayed by approximately 1.5, 3, 2, and 3 hours, respectively, under nonfasting conditions compared to fasting conditions (Table 3; Figure 1B–E). Bioequivalence Assessment for Elagolix Capsules (Study 1) and Elagolix/E2/NETA FDC Capsule (Study 2) The mean (SD) elagolix plasma concentration-time profiles in Studies 1 and 2 are presented in Figure 2. In Study 1, under fasting conditions, the test elagolix 300-mg capsule formulation was bioequivalent to the reference elagolix 300-mg tablet formulation, as the 90% CI for geometric mean ratio of Cmax and AUCinf were within the range of 0.80-1.25 (Table 4). Similarly, in Study 2 under fasting conditions the test elagolix/E2/NETA (300-mg/1-mg/0.5-mg) FDC capsule and the reference coadministered elagolix 300-mg tablet and E2/NETA (1-mg/0.5-mg) tablet encapsulated were bioequivalent. The 90% CI for geometric mean ratio of Cmax and AUCinf for elagolix, norethindrone, total estrone (baseline-adjusted), and unconjugated estradiol (baseline-adjusted) were all within the 0.80-1.25 range (Table 4). | Fed or fasting conditions | Parameter | Elagolixa | Elagolixb | Norethindroneb | Total estrone Baseline-adjustedb | Unconjugated estradiol Baseline-adjustedb | |---|---|---|---|---|---|---| | Fasting conditions | T/R Cmax | 0.87 (0.81-0.94) | 0.91 (0.87-0.95) | 1.12 (1.08-1.15) | 1.02 (0.96-1.08) | 0.95 (0.91-0.98) | | T/R AUCinf | 0.97 (0.93-1.01) | 0.97 (0.95-1.00) | 0.96 (0.94-0.98) | 0.93 (0.87-1.00) | 0.91 (0.88-0.95) | | Fed or fasting conditions | Parameter | Elagolixc | Elagolixd | Norethindroned | Total estrone Baseline-adjustedd | Unconjugated estradiol Baseline-adjustedd | |---|---|---|---|---|---|---| | Fed conditions | T/R Cmax | 0.60 (0.48-0.74) | 0.64 (0.51-0.81) | 0.50 (0.43-0.59) | 0.56 (0.45-0.69) | 0.77 (0.65-0.91) | | T/R AUCinf | 0.72 (0.66-0.79) | 0.75 (0.66-0.84) | 1.23 (1.14-1.32) | 0.86 (0.79-0.94) | 1.05 (0.96-1.14) | - AUCinf, area under the plasma concentration-time curve from time 0 to infinity; BE, bioequivalence; Cmax, maximum concentration; CI, confidence interval; E2, estradiol; FDC, fixed-dose combination; NETA, norethindrone acetate; T/R, test/reference. - BE assessment: Geometric mean ratio (90% CI) of T/R for Cmax and AUCinf were calculated. - a Test: elagolix capsule; reference: elagolix tablets (BE Study 1). - b Test: elagolix/E2/NETA FDC capsule; reference: co-administered elagolix and E2/NETA tablets (BE Study 2). - c Administered with elagolix capsule (BE Study 1). - d Administered with elagolix/E2/NETA FDC capsule (BE Study 2). Safety The regimens tested were generally well tolerated in both studies. No clinically significant abnormalities in vital signs, ECGs, physical examinations, or laboratory measurements were observed. In Study 1, 1 subject discontinued study drug due to gastroenteritis. Two subjects had adverse events of special interest, mild affect lability (resolved after 4 days) and mild depressed mood (resolved after 1 day). Treatment-emergent adverse events in Study 1 are summarized Table S4. In Study 2, 3 subjects were discontinued from the study due to mild adverse events of oropharyngeal pain, upper respiratory tract infection, and constipation. Treatment-emergent adverse events reported by 5 or more subjects in Study 2 are summarized in Table S5. No new safety concerns were identified in either study.

This is the first study to compare the pharmacokinetics of the elagolix/E2/NETA FDC capsule (300 mg/1 mg/0.5 mg) with coadministered individual drugs under fasting conditions in healthy postmenopausal women. The PK analysis demonstrated that the elagolix FDC capsule is bioequivalent to individual tablet drugs, and thus it is expected that the elagolix FDC capsule would provide the same therapeutic effects as coadministration of the individual drugs. It is generally believed that demonstrating BE between an FDC product and the individual mono-product is significantly more challenging than demonstrating BE of different formulations of a single active pharmaceutical ingredient (API),15 considering at least the following facts: (1) the potential complexity of disposition profiles for multiple APIs in FDC products if 1 API interacts with another API in vivo; and (2) the complexity of clinical study design, such as sample size, fasting/fed state, and/or study populations to enable achieving BE for multiple APIs within 1 FDC product in 1 crossover study. Since 3 APIs are included in elagolix/E2/NETA FDC capsule, BE acceptance criteria are set on the basis of all APIs in FDC capsules. Our results showed that the 90% CI around the test-to-reference geometric mean ratio of elagolix, norethindrone, and baseline-adjusted total estrone were all within the BE acceptance limits of 0.8-1.25 for both Cmax and AUCinf (Table 4). These findings suggested that administration of elagolix/E2/NETA (300-mg/1-mg/0.5-mg) FDC capsule did not significantly impact the PK of E2/NETA in the presence of elagolix exposure and the PK of elagolix in the presence of E2/NETA exposure, and thus supported bridging of the Phase 3 coadministered tablets. Another key challenge to demonstration of bioequivalence for elagolix/E2/NETA FDC capsule is the sample size. The 2 studies were designed to provide sufficient statistical power for each of the analytes (elagolix, norethindrone, total estrone, and unconjugated estradiol) for both Cmax and AUC with a crossover design where subjects served as their own control. The variable that had the largest intrasubject variability was used for sample size justifications, as the width of a 90% CI for a ratio of point estimates was calculated on the basis of the intrasubject variability. Among all the analytes and PK parameters, elagolix Cmax appeared to have the highest intravariability (thus the widest 90% CI) based on previous AbbVie studies and the literature.16 The intrasubject coefficient of variation for elagolix Cmax was estimated to be 27%, which was slightly lower than that of a highly variable drug, defined as greater than 30% intrasubject coefficient of variation.17 Therefore, 90% CI for meeting rigorous 0.8-1.25 criteria were performed. It should be noted that the study populations of these 2 BE studies are different. The study population for assessing BE of elagolix/E2/NETA FDC capsule was postmenopausal women aged 55-70 years per study protocol, to limit variations of E2 due to menstrual cycling. This is one of the limitations of the present studies due to product-specific consideration. The study population for assessing BE of elagolix capsules was healthy premenopausal women. Population PK analysis of elagolix demonstrated that elagolix PK were not affected by patient demographics and were similar between healthy women and women with endometriosis.18 It is known that food might affect oral drug absorption by delaying gastric emptying time, altering gastrointestinal pH, stimulating bile flow, or physically interacting with drug, and subsequently change the PK of drugs.19 We showed in this study that the impacts of a high-fat meal on the disposition of elagolix FDC capsule and elagolix capsule were small, with the highest impact on reducing mean Cmax of NETA by 51% (Table 3). Of note, although the elagolix AUCinf was decreased by approximately 28% for the elagolix FDC capsule and the elagoix capsule in fed conditions compared to fasting conditions, elagolix clinical efficacy results from all Phase 3 studies 20, 21 were similar, regardless of drug administration with respect to meals,22 suggesting that the elagolix FDC capsule and elagolix capsules could be taken with or without food. In addition, elagolix population PK modeling did not show any patient-related factors that would require dose adjustments for the approved dosage of 300 mg elagolix twice daily with estradiol 1 mg/norethindrone acetate 0.5 mg daily in women with heavy menstrual bleeding associated with uterine fibroids.23 The totality of results obtained from those 2 BE studies and previously established elagolix population PK models support that the elagolix/E2/NETA FDC capsule may provide improved compliance for patients in the management of moderate to severe endometriosis pain, and the results from these BE studies together with established elagolix physiologically based PK modeling24, 25 could extend the utility of elagolix physiologically based PK model not only for in silico drug-drug interaction assessment but also for BE assessments.

Our results demonstrate that the elagolix FDC capsule is bioequivalent to the coadministered elagolix 300-mg tablet and E2/NETA 1/0.5 mg tablet, supporting the bridging of the formulations used in the Phase 3 study. Acknowledgments Medical writing support was provided by Wesley Wayman, PhD, an employee of AbbVie. Conflicts of Interest This study was supported by AbbVie Inc. AbbVie contributed to the study design; research; interpretation of the data; and writing, review, and approval of the manuscript. All authors are current AbbVie employees and may hold AbbVie stock or options. Data Availability Statement AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (eg, protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan, and execution of a Data Sharing Agreement. Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this article for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/, then select “Home.”