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.
CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e11; doi:10.1038/psp.2012.10; advance online publication 17 October 2012.