Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women

Ng, Juki; Chwalisż, Kristof; Carter, David C; Klein, Colin

doi:10.1210/jc.2016-3845

Cited by 93 publications

(122 citation statements)

References 20 publications

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“…25 Although women were instructed to use dual nonhormonal contraception, pregnancies were reported during the trials. There were no anomalous outcomes in the elagolix groups in these trials, but no conclusion on the effect of elagolix on pregnancy could be made, owing to the small number of pregnancies.…”

Section: Discussionmentioning

confidence: 99%

“…Observed reductions in pain and reports of hypoestrogenic adverse events were consistent with the mechanism of action of elagolix, which competitively inhibits GnRH receptors in the pituitary gland and leads to a rapid reduction in circulating gonadotropins and estradiol. 25 This mechanism is different from that of GnRH agonists, which after an initial stimulatory phase desensitize GnRH receptors in the pituitary and subsequently cause depletion of pituitary gonadotropins and full suppression of estradiol to levels that are equivalent to those associated with bilateral oophorectomy. 33 Agonists are effective in reducing both dysmenorrhea and nonmenstrual pelvic pain in women with endometriosis.…”

Section: Discussionmentioning

confidence: 99%

“…[22][23][24] A phase 1 study showed that elagolix (at a dose of 200 mg twice daily) led to nearly full estrogen suppression. 25 We performed two similar multicenter, doubleblind, randomized, placebo-controlled, phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) of 6-month treatment with elagolix at two doses in women with moderate or severe endometriosis-associated pain.…”

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confidence: 99%

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Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist

et al. 2017

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist

et al. 2017

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“…At a dose of 150 mg once daily, elagolix suppresses E2 to early follicular phase levels (approximately 50 pg/mL) in most women. In a phase 1 study, at a dose of 200 mg twice daily, elagolix led to nearly full suppression of E2 to levels observed during menses (less than 20 pg/mL) in most women …”

mentioning

confidence: 99%

“…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 . The 2 doses of elagolix were associated with dose‐dependent hypoestrogenic adverse effects (eg, higher rates of hot flushes that were mostly mild or moderate, higher levels of serum lipids, and greater decreases from baseline in bone mineral density compared with placebo) …”

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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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Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure

Mukherjee

Chiney

Shao

et al. 2022

Biopharm & Drug Disp

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The aim of this analysis was to use a physiologically based pharmacokinetic (PBPK) model to predict the impact of changes in dissolution rates on elagolix exposures and define clinically relevant acceptance criteria for dissolution. Varying in vitro dissolution profiles were utilized in a PBPK model to describe the absorption profiles of elagolix formulations used in Phase 3 clinical trials and for the to be marketed commercial formulations. Single dose studies of 200 mg elagolix formulations were used for model verification under fasted conditions. Additional dissolution scenarios were evaluated to assess the impact of dissolution rates on elagolix exposures. Compared to the Phase 3 clinical trial formulation, sensitivity analysis on dissolution rates suggested that a hypothetical scenario of ∼75% slower dissolution rate would result in 14% lower predicted elagolix plasma exposures, however, the predicted exposures are still within the bioequivalence boundaries of 0.8-1.25 for both C max and AUC. A clinically verified PBPK model of elagolix was utilized to evaluate the impact of wider dissolution specifications on elagolix plasma exposures. The simulation results indicated that a slower in vitro dissolution profile, would not have a clinically significant impact on elagolix exposures. These model results informed the setting of wider dissolution specifications without requiring in vivo studies.

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Dose-Dependent Suppression of Gonadotropins and Ovarian Hormones by Elagolix in Healthy Premenopausal Women

Cited by 93 publications

References 20 publications

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment

Physiologically based pharmacokinetic modeling and simulations to inform dissolution specifications and clinical relevance of release rates on elagolix exposure

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