Aole Zheng1, Wen Yao Mak1, Muyesaier Alifu1, Xiaoqiang Xiang1
1Fudan University
Introduction The world’s demographic is shifting rapidly with individuals aged 65 and older projected to reach 2.2 billion by the late 2070s[1]. As the number of postmenopausal women increases, adequate management of postmenopausal conditions becomes a public health priority. Simultaneously, persistent low fertility rates and delayed parenthood in developed countries have contributed to changing patterns childbirth and warrant effective interventions to mitigate adverse economic and societal consequences. . Homeostasis in the estradiol (E2) and progesterone (P4) dynamics is critical for the management of postmenopausal conditions, as well as to adequately prepare for assist reproduction in older women who still wish to conceive[2, 3]. Therefore, understanding the pharmacokinetic (PK) behavior of natural E2 and P4, as well as the feedback mechanisms of the hormonal axis following drug administration, is essential for optimizing hormone replacement therapy and in vitro fertilization strategies. Objectives 1. To comprehensively analyze the PK behavior of natural E2 and P4 following different administration routes (oral and vaginal) using a physiologically based pharmacokinetic (PBPK) and quantitative systems pharmacology (QSP) models. 2. To quantitatively describe the feedback and negative feedback regulation of other gonadotropins after E2 and P4 administration, providing a mechanistic explanation for hormonal changes and follicular growth. 3. To evaluate various clinical dosing regimens for postmenopausal women and women with ovulation difficulties, offering guidance for precision medicine in clinical practice. Methods 1. A PBPK model for E2 and P4 was developed and validated in PK-Sim to describe the PK behavior following exogenous oral administration. 2. A virtual female individual incorporating four additional compartments—breast tissue, endometrium, myometrium, and vagina—was constructed in Mobi. Based on this model, a vaginal absorption and metabolism PBPK model was developed and validated for E2 and P4 to describe their PK behavior following exogenous vaginal administration. 3. A published QSP models[4] were applied to simulate endogenous hormonal changes in women with normal menstrual cycles, ovulatory dysfunction, and postmenopausal conditions using MATLAB. The integration of PBPK and QSP models enabled a comprehensive evaluation of various clinical regimens. Results The PBPK model demonstrated reliable prediction performance, with the geometric mean fold error (GMFE) for estradiol’s AUC and Cmax being 0.89 and 0.94, respectively, and for progesterone, 1.23 and 0.82, in oral administration. In the vaginal PBPK model, the GMFE for estradiol’s AUC and Cmax was 1.00 and 0.93, and for progesterone, 0.90 and 0.79. The QSP models adequately predicted endogenous hormonal PK behavior and follicular growth across different populations, including women with normal menstrual cycles, ovulatory dysfunction, and postmenopausal women. The combined PBPK-QSP model successfully simulated common E2 or P4 treatment regimens, providing actionable insights to clinical decision-making: (1) For postmenopausal women, a regimen involving continuous administration of estradiol for two weeks followed by dose reduction appeared optimal; (2) For women with ovulation difficulties undergoing luteal support therapy, increasing the dose of vaginal tablets or the frequency of vaginal suppositories was recommended for getting target concentration. Conclusions The PBPK model effectively predicted the PK behavior of exogenous hormones, while the QSP model simulated cyclic changes in endogenous hormones and follicular dynamics across different populations. The combined PBPK-QSP model provided a quantitative description of the overall PK changes and hormonal axis feedback mechanisms following exogenous hormone administration, offering valuable insights for optimizing clinical precision medicine.
[1] COOMARASAMY A, DEVALL A J, BROSENS J J, et al. Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence [J]. American Journal of Obstetrics and Gynecology, 2020, 223(2): 167-76. [2] PINKERTON J V. Hormone Therapy for Postmenopausal Women [J]. New England Journal of Medicine, 2020, 382(5): 446-55. [3] DAYA S. Luteal support: progestogens for pregnancy protection [J]. Maturitas, 2009, 65 Suppl 1: S29-34. [4] FISCHER-HOLZHAUSEN S, RöBLITZ S. Hormonal regulation of ovarian follicle growth in humans: Model-based exploration of cycle variability and parameter sensitivities [J]. Journal of Theoretical Biology, 2022, 547: 111150.
Reference: PAGE 33 (2025) Abstr 11770 [www.page-meeting.org/?abstract=11770]
Poster: Drug/Disease Modelling - Endocrine