Clinical Pharmacokinetics (2020) 59:297–309 https://doi.org/10.1007/s40262-019-00840-7 REVIEW ARTICLE Clinical Pharmacology of Elagolix: An Oral Gonadotropin‑Releasing Hormone Receptor Antagonist for Endometriosis Mohamad Shebley1 · Akshanth R. Polepally1 · Ahmed Nader1 · Juki W. Ng2 · Insa Winzenborg1 · Cheri E. Klein1 · Peter Noertersheuser1 · Megan A. Gibbs1 · Nael M. Mostafa1 Published online: 21 November 2019 © The Author(s) 2019 Abstract The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endome- triosis. Elagolix pharmacokinetics (PK) show signifcant population variability, however they are minimally afected by patients’ baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) efects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the beneft–risk profle of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the efectiveness of the approved dosages and provided general dosing instructions of the frst approved oral gonadotropin-releasing hormone receptor antagonist. Key Points 1 Introduction Elagolix is the frst approved oral gonadotropin-releasing Elagolix (Orilissa™) is a novel, non-peptide oral, short-act- hormone (GnRH) receptor antagonist for moderate to ing competitive gonadotropin-releasing hormone (GnRH) severe pain associated with endometriosis. receptor antagonist approved by the US FDA for the man- agement of moderate to severe pain associated with endome- The clinical pharmacology profle of elagolix was triosis [1], and is currently in development for the manage- fully characterized in several Phase 1 PKPD studies ment of heavy menstrual bleeding associated with uterine along with several model informed drug development fbroids [2, 3]. Both endometriosis and uterine fbroids are approaches. estrogen-dependent conditions [2, 4], and elagolix sup- This comprehensive description of the clinical pharma- presses gonadotropin hormones and ovarian estrogen pro- cology attributes of elagolix provides a reference for duction in a dose-dependent manner, modulating circulating prescribers and clinical pharmacologists who seek to use estrogen levels from partial suppression of estradiol (E2) at or understand the clinical PKPD properties of elagolix. lower doses to nearly full suppression at higher doses [5, 6]. This is in contrast to GnRH receptor agonists, which, after Electronic supplementary material The online version of this an initial stimulatory phase (fare efect), desensitize the article (https ://doi.org/10.1007/s4026 2-019-00840 -7) contains pituitary GnRH receptors and lead to profound suppression supplementary material, which is available to authorized users. of ovarian sex steroid secretion similar to that of ovariecto- * Mohamad Shebley mized women [6]. [email protected] The clinical development program for elagolix included several clinical pharmacology studies, which enabled full 1 Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL 60064, USA characterization of the pharmacokinetics (PK), pharmaco- dynamics (PD), efects of intrinsic and extrinsic factors, and 2 Pharmaceutical Development, General Medicine, AbbVie Inc., North Chicago, IL, USA population PK/PD, exposure–response (safety and efcacy) Vol.:(0123456789) 298 M. Shebley et al. analyses and physiologically based PK (PBPK) modeling MoA and downstream efects on gonadotropins and ovarian and simulation. A summary of the extensive data, analyses, hormones is shown in Fig. 1. and conclusions generated from these studies is presented herein to ofer a comprehensive overview of the clinical pharmacology attributes of elagolix. 3 Pharmacokinetics (PK) of Elagolix 3.1 Absorption 2 Mechanism of Action of Elagolix Elagolix sodium is a non-peptide, orally bioavailable small Elagolix is a highly potent (KD = 54 pM) GnRH receptor molecule, amorphous solid that is freely soluble in water. antagonist that inhibits endogenous GnRH signaling by At either the 150 or 200 mg dose, elagolix is highly solu- binding competitively to GnRH receptors in the anterior ble per the Biopharmaceutics Classifcation System (BCS) pituitary gland [7]. Elagolix mechanism of action (MoA) is throughout the physiological pH range, it exhibits high diferent from long-acting GnRH receptor agonists, which aqueous solubility (approximately 1 mg/mL), is a zwitte- induce 1–2 weeks of ‘fare-up’ by downregulating GnRH rion with pKa 4.0 (acid) and 7.9 (base), and has an apparent receptors [6]. The competitive nature of elagolix competitive low to moderate permeability (0.5–2.8 × 10−6 cm/s) based on antagonism of the GnRH receptors provides an advantage in vitro Caco-2 studies [7]. These data suggest that elagolix by allowing for rapid and reversible onset and ofset, and could be classifed as a BCS class III drug. Elagolix con- hence more fexibility in modulating the hypothalamic–pitu- tains one chiral center and is manufactured exclusively as itary–gonadal axis. An illustration that describes elagolix the (R)-isomer. The structural formula of elagolix sodium is shown in Fig. 2. Fig. 1 Illustration of GnRH action and function during the normal stream dose-dependent efects on circulating estradiol levels in blood. female menstrual cycle, elagolix mechanism of GnRH receptors’ GnRH gonadotropin-releasing hormone competitive antagonism at the anterior pituitary gland, and its down- Clinical Pharmacology Profle of Elagolix 299 AUC from time zero to infnity (AUC∞ ) of 432.7, 411.8, and 443.9 ng∙h/mL, respectively. However, the geomean AUC ∞ for the colon administration was only 35.22 ng∙h/mL, repre- senting < 10% that of the same dose deposited into the stom- ach/duodenum, jejunum, or ileum, and with a mean Cmax for the colon administration at approximately 38 times lower than that following administration into the ileum (Electronic Supplementary Fig. 1). Several elagolix formulations ranging from suspension to modifed and immediate-release (IR) tablets were evalu- ated throughout the development program and across mul- tiple phase I studies. While variability in the PK profles of elagolix was observed across the tested formulations, the Fig. 2 Structure of elagolix sodium; molecular weight of 653.58. exposures did not vary signifcantly, consistent with a char- Elagolix free acid has a molecular weight of 631.60 acteristic BCS III behavior. An IR tablet formulation was chosen for the endometriosis phase III studies, as well as In clinical PK studies in healthy subjects, elagolix absorp- for the commercial formulation. The fnal commercial tablet tion is rapid, with a time to maximum concentration (Tmax) formulation of elagolix is bioequivalent to the phase III tab- of approximately 1 h. Elagolix exposure (maximum con- let formulation. Representative PK profles of the phase III centration [Cmax] and area under the curve [AUC]) is dose and commercial 200 mg IR tablet formulations is shown in proportional from 100 to 400 mg twice daily [5], and more Fig. 3. Elagolix 150 mg once-daily and 200 mg twice-daily than dose proportional with single doses of 600–1200 mg. A PK parameters at steady state are summarized in Table 1. regional absorption study was conducted in six healthy sub- Dose proportional PK are demonstrated for both elagolix jects to characterize the PK of elagolix 100 mg administered dosages based on the dose normalized Cmax and AUC values; to the stomach via oral solution, and to the jejunum, ileum, elagolix does not accumulate with repeated once daily or and colon via a radiolabeled remote drug delivery capsule twice daily dosing. (InteliSite®). Based on the geometric mean AUC values, elagolix doses delivered as either a solution to the stomach 3.2 Food Efect or in an InteliSite® capsule to the jejunum and ileum resulted in comparable overall systemic exposure, with a geomean The efect of food on elagolix plasma exposure was assessed following administration of a high-fat meal in a pivotal phase Fig. 3 Elagolix plasma con- centration–time profles of the phase III and commercial for- mulations of Orilissa. Symbol represents the mean 300 M. Shebley et al. Table 1 Mean (percentage coefcient of variation) pharmacokinetic scenario for the efect of food on elagolix exposure, and due parameters at steady state of elagolix 150 mg qd or 200 mg bid to the lack of clinical signifcance of the small reduction in Pharmacokinetic parameters 150 mg qd 200 mg bid elagolix exposure with meals, elagolix was administered without regard to meals in the fourth endometriosis phase III T a max (h ) 1.0 (0.5–1.0) 1.0 (0.5–1.5) extension trial. Elagolix clinical efcacy results from all the C max (ng/mL) 574