Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis

Winzenborg, Insa; Nader, Ahmed; Polepally, Akshanth R.; Liu, Mohan; Degner, Jacob F.; Klein, Colin; Mostafa, Nael M.; Noertersheuser, Peter; Ng, Juki

doi:10.1007/s40262-018-0629-6

Cited by 22 publications

(44 citation statements)

References 12 publications

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“…The minor urinary excretion of radioactivity was consistent with the population PK analysis, where renal function was not associated with elagolix PK parameters [8]. The OATP1B1 genotype was a statistically significant covariate on apparent clearance (CL/F), however the small change in CL/F (14%) was not considered clinically relevant when the poor and intermediate transporter genotypes were combined and compared with the extensive transporter genotype [8]. Figure 6 depicts the disposition and elimination mechanisms of elagolix in humans.…”

Section: Eliminationsupporting

confidence: 83%

“…The disposition of elagolix involves OATP1B1, and higher (less than twofold) plasma concentrations of elagolix were observed in groups of patients and healthy subjects who have two reduced function alleles of the gene that encodes OATP1B1 (SLCO1B1 521T > C). The frequency of this SLCO1B1 521 C/C genotype is generally < 5% in most racial/ethnic groups [8]. The lack of clinical relevance of OATP1B1 genotypes on elagolix exposure is discussed in a later section on population PK analysis.…”

Section: Pharmacogeneticsmentioning

confidence: 99%

“…Elagolix is moderately (80%) bound to human plasma proteins, and preferentially partitions into plasma rather than blood cellular components, with blood-to-plasma ratios of 0.6 [1]. Based on population PK analyses using data from five phase I healthy volunteers and four phase III endometriosis patient studies, the elagolix estimated apparent central volume of distribution (V c /F) was 257 L [8]. Elagolix is a substrate of the hepatic uptake transporter organic anion transporting polypeptide (OATP) 1B1 based on in vitro studies [10], pharmacogenetics analysis of OATP1B1 variants [8], and clinical drug-drug interactions (DDIs) with singledose rifampin [16]; however, population PK analysis did not identify the OATP1B1 genotype as a significant covariate on elagolix V c /F [8].…”

Section: Distributionmentioning

confidence: 99%

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Clinical Pharmacology of Elagolix: An Oral Gonadotropin-Releasing Hormone Receptor Antagonist for Endometriosis

et al. 2019

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The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected 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) effects 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 benefit-risk profile 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 effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist.

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Section: Eliminationsupporting

confidence: 83%

Section: Pharmacogeneticsmentioning

confidence: 99%

Section: Distributionmentioning

confidence: 99%

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Clinical Pharmacology of Elagolix: An Oral Gonadotropin-Releasing Hormone Receptor Antagonist for Endometriosis

et al. 2019

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“…Inhibition of intestinal P‐glycoprotein by elagolix modestly increased digoxin concentrations, with C max increased by approximately 70% and AUC increased by approximately 30% . The population pharmacokinetics of elagolix suggested the only covariate affecting elagolix apparent clearance was OATP1B1, although this covariate did not result in a clinically meaningful change in elagolix plasma exposure . Strong inhibitors of OATP1B1 are contraindicated to be coadministered with elagolix …”

mentioning

confidence: 99%

“…7 The population pharmacokinetics of elagolix suggested the only covariate affecting elagolix apparent clearance was OATP1B1, although this covariate did not result in a clinically meaningful change in elagolix plasma exposure. 10 Strong inhibitors of OATP1B1 are contraindicated to be coadministered with elagolix. 1 In 2 large replicate phase 3 trials, both 150-mg once-daily and 200-mg twice-daily doses of elagolix were found to be safe and effective in improving both dysmenorrhea and nonmenstrual associated pelvic pain in women with endometriosis-associated pain.…”

mentioning

confidence: 99%

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment

Duan

Marbury

et al. 2018

Clinical Pharm in Drug Dev

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The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin‐releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic). Intensive pharmacokinetic blood samples were collected. Elagolix exposures were comparable in women with normal renal function and those with moderate/severe renal impairment or end‐stage renal disease. Elagolix exposures also appeared to be similar in women with normal hepatic function and women with mild hepatic impairment. Elagolix area under the curve in women with moderate hepatic impairment and with severe hepatic impairment was approximately 3‐fold and 7‐fold higher than in women with normal hepatic function. The adverse event incidence was low, with the main events being mild nausea and headache. No dosage adjustment was needed in women with renal impairment or women with mild hepatic impairment. Although an elagolix dose of 150 mg once daily may be used in women with moderate hepatic impairment for up to 6 months, this elagolix dose should not be used in women with severe hepatic impairment.

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

Chen,

Marroum,

Chiu

et al. 2024

Clinical Pharm in Drug Dev

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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.

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Population Pharmacokinetics of Elagolix in Healthy Women and Women with Endometriosis

Abstract: Elagolix pharmacokinetics were not affected by patient demographics and were similar between healthy women and women with endometriosis. Clinical Trial Registration Numbers NCT01403038, NCT01620528, NCT01760954, NCT01931670, NCT02143713.

Cited by 22 publications

References 12 publications

Clinical Pharmacology of Elagolix: An Oral Gonadotropin-Releasing Hormone Receptor Antagonist for Endometriosis

Clinical Pharmacology of Elagolix: An Oral Gonadotropin-Releasing Hormone Receptor Antagonist for Endometriosis

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment

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

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