Elagolix

Elagolix is a GnRH receptor antagonist that 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 (LH) and follicle-stimulating hormone (FSH), leading to decreased blood concentrations of the ovarian sex hormones, estradiol and progesterone.

Effect on Ovulation and Estradiol

In a 3-menstrual cycle study in healthy women, elagolix 150 mg once daily and 200 mg twice daily resulted in an ovulation rate of approximately 50% and 32%, respectively. In the Phase 3 trials in women with endometriosis, elagolix caused a dose-dependent reduction in median estradiol concentrations to approximately 42 pg/mL for 150 mg once daily regimen and 12 pg/mL for the 200 mg twice daily regimen.

Cardiac Electrophysiology

The effect of elagolix on the QTc interval was evaluated in a randomized, placebo- and positive-controlled, open-label, single-dose, crossover thorough QTc study in 48 healthy adult premenopausal women. Elagolix concentrations in subjects given a single dose of 1200 mg was 17-times higher than the concentration in subjects given elagolix 200 mg twice daily. There was no clinically relevant prolongation of the QTc interval.

The pharmacokinetic properties of elagolix in healthy subjects are summarized in Table 8. The steady state pharmacokinetic parameters under fasting conditions are summarized in Table 9.

Table 8. Pharmacokinetic Properties of Elagolix in Healthy Subjects:

Table 9. Mean (%CV) Steady State Pharmacokinetic Parameters of Elagolix:

CV: Coefficient of variation
C_max: peak concentration
AUC_τ: area under the plasma concentration-time curve during the dosing interval (τ) i.e., 12 hours for twice daily regimen, 24 hours for once daily regimen.
CL/F: oral clearance
V_dss/F: apparent volume of distribution at steady state
R_ac: drug accumulation ratio

Specific Populations

Patients with Renal Impairment

Elagolix exposures (C_max and AUC) are not altered by renal impairment. The mean exposures are similar for women with moderate to severe or end stage renal disease (including women on dialysis) compared to women with normal renal function.

Patients with Hepatic Impairment

Elagolix exposures (C_max and AUC) are similar between women with normal hepatic function and women with mild hepatic impairment. Elagolix exposures in women with moderate and severe hepatic impairment are approximately 3-fold and 7-fold, respectively, higher than exposures from women with normal hepatic function.

Racial or Ethnic Groups

No clinically meaningful difference in the pharmacokinetics of elagolix between White and Black subjects or between Hispanics and others was observed. There is no clinically meaningful difference in the pharmacokinetics of elagolix between Japanese and Han Chinese subjects.

Body weight/Body mass index

Body weight or body mass index does not affect the pharmacokinetics of elagolix.

Drug Interaction Studies

Drug interaction studies were performed with elagolix and other drugs that are likely to be co-administered and with drugs commonly used as probes for pharmacokinetic interactions. Tables 10 and 11 summarize the pharmacokinetic effects when elagolix was co-administered with these drugs.

Table 10. Drug Interactions: Change in Pharmacokinetics of Elagolix in the Presence of Co-administered Drugs:

CI: Confidence interval
^* ratios for C_max and AUC compare co-administration of the medication with elagolix vs. administration of elagolix alone.
^# A single dose of 600 mg rifampin inhibits OATP1B1; 600 mg once daily dose of rifampin inhibits OATP1B1 and induces CYP3A.

No clinically significant changes in elagolix exposures were observed when co-administered with rosuvastatin (20 mg once daily), sertraline (25 mg once daily) or fluconazole (200 mg single dose).

Table 11. Drug Interactions: Change in Pharmacokinetics of Co-administered Drug in the Presence of Elagolix:

CI: Confidence interval
^* ratios for C_max and AUC compare co-administration of the medication with elagolix vs. administration of the medication alone.
^a metabolite of norgestimate

No clinically significant changes were observed in exposures of sertraline, fluconazole, or bupropion when co-administered with elagolix 300 mg twice daily.