Integrated Pharmacometrics and Systems Pharmacology Model-Based Analyses to Guide GnRH Receptor Modulator Development for Management of Endometriosis

Endometriosis is a gynecological condition resulting from proliferation of endometrial-like tissue outside the endometrial cavity. Estrogen suppression therapies, mediated through gonadotropin-releasing hormone (GnRH) modulation, decrease endometriotic implants and diminish associated pain albeit at the expense of bone mineral density (BMD) loss. Our goal was to provide model-based guidance for GnRH-modulating clinical programs intended for endometriosis management. This included developing an estrogen suppression target expected to provide symptomatic relief with minimal BMD loss and to evaluate end points and study durations supportive of efficient development decisions. An existing multiscale model of calcium and bone was adapted to include systematic estrogen pharmacologic effects to describe estrogen concentration-related effects on BMD. A logistic regression fit to patient-level data from three clinical GnRH agonist (nafarelin) studies described the relationship of estrogen with endometrial-related pain. Targeting estradiol between 20 and 40 pg/ml was predicted to provide efficacious endometrial pain response while minimizing BMD effects.