Elagolix is the first approved oral gonadotropin-releasing hormone (GnRH) receptor antagonist for moderate to severe pain associated with endometriosis. |
The clinical pharmacology profile of elagolix was fully characterized in several Phase 1 PKPD studies along with several model informed drug development approaches. |
This comprehensive description of the clinical pharmacology attributes of elagolix provides a reference for prescribers and clinical pharmacologists who seek to use or understand the clinical PKPD properties of elagolix. |
1 Introduction
2 Mechanism of Action of Elagolix
3 Pharmacokinetics (PK) of Elagolix
3.1 Absorption
Pharmacokinetic parameters | 150 mg qd | 200 mg bid |
---|---|---|
Tmax (ha) | 1.0 (0.5–1.0) | 1.0 (0.5–1.5) |
Cmax (ng/mL) | 574 (29) | 774 (68) |
AUCτ (ng × h/mL) | 1292 (31) | 1725 (57) |
t½ (hb) | 6.42 ± 3.20 | 4.29 ± 0.47 |
CL/F (L/h) | 123 (21) | 144 (43) |
Vss/F (L) | 1674 (94) | 881 (38) |
Rac | 0.98 (7) | 0.89 (19) |
Cmax/dose | 3.83 (29) | 3.87 (68) |
AUCτ/dose | 8.61 (31) | 8.62 (57) |
3.2 Food Effect
3.3 Distribution
3.4 Metabolism
3.5 Elimination
4 Pharmacodynamics of Elagolix
4.1 Effects on Hormones, Folliculogenesis, and Ovulation
4.2 QT Interval
5 Intrinsic Factors
5.1 Race/Ethnicity
5.2 Renal Function
5.3 Hepatic Function
5.4 Pharmacogenetics
6 Extrinsic Factors
6.1 Mechanism-Based Drug–Drug Interactions (DDIs)
6.2 Elagolix as a Victim of Cytochrome P450 s (CYPs) and Transporter-Mediated DDIs
6.3 Elagolix as a Perpetrator of CYPs and Transporter-Mediated DDIs
6.4 DDIs with Oral Contraceptives
6.5 DDIs with Commonly Coadministered Drugs
7 Population PK Analyses
8 Physiologically Based PK Analyses
9 Exposure–Response Relationship
9.1 Exposure–Efficacy Analysis for Dose Justification
9.2 Exposure–Safety Analysis to Support the Duration of Treatment
Month | Percentage change from baseline in lumbar spine BMD [mean (95% CI)] | |||
---|---|---|---|---|
150 mg qd | 200 mg bid | |||
Model | Observeda | Model | Observeda | |
6 | – 0.6 (– 1.1 to – 0.2) | – 0.3, – 0.7 | – 1.6 (– 2.0 to – 1.2) | – 2.6, – 2.5 |
12 | – 1.1 (– 1.5 to – 0.5) | – 0.6, – 1.1 | – 2.7 (– 3.3 to – 2.2) | – 3.6, – 3.9 |
24 | – 1.6 (– 2.3 to – 0.9) | NA | – 4.3 (– 5.2 to – 3.7) | NA |
36 | – 1.9 (– 2.9 to – 1.2) | NA | – 5.2 (– 6.2 to – 4.3) | NA |