Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis

Sven Stodtmann, Ahmed Nader, Akshanth R Polepally, Ahmed A Suleiman, Insa Winzenborg, Peter Noertersheuser, Juki Ng, Nael M Mostafa, Mohamad Shebley
Clinical and translational science · 2021 · vol. 14(4) , pp. 1611–1619 · doi:10.1111/cts.13040 · W3157322789
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A quantitative systems pharmacology model linked elagolix's dose-dependent estradiol suppression to bone mineral density changes, successfully validating predictions against Phase 3 endometriosis trial data.

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Abstract

Abstract Elagolix is a novel, oral gonadotropin‐releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose‐dependent suppression of estradiol (E2) in clinical studies. A dose‐response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross‐linked telopeptide of type 1 collagen [CTX]), formation (N‐terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in −0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.

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Condition tags

mesh:D004715endometriosis

MeSH descriptors

Bone Density Calcium Endometriosis Hydrocarbons, Fluorinated Network Pharmacology Pyrimidines Adolescent Adult Bone Density Bone Density Calcium Clinical Trials as Topic Computer Simulation Dose-Response Relationship, Drug Drug Administration Schedule Endometriosis Endometriosis Endometriosis Estradiol Estradiol

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