Sophie Fischer-Holzhausen1, Nina Nauwelaerts1, Leonie Lautz1, Stephan Schaller1, Marco Siccardi1
1ESQlabs GmbH
Introduction: The Female Reproductive Tract (FRT) refers to several connected internal organs that maintain the female reproductive function. Infections, cancer, and chronic diseases such as endometriosis and polycystic ovarian syndrome can affect the function of the female reproductive system. Such conditions often require medical care to manage symptoms and avoid complications. Therefore, effective treatment options are essential to accommodate patient needs. Physiologically-based (Pharmaco-)Kinetic (PB(P)K) modeling is an established tool to support drug development. However, the FRT is usually not presented in modeling platforms, and FRT tissues drug penetration is not commonly investigated and predicted. The development of a PB(P)K model structure giving a detailed representation of the FRT can positively contribute to drug development for treatments in the women’s health space. The tissue and fluid predictions delivered by such a model can support the development of drugs administered via vaginal and uterine routes as well as systemic treatments. Objectives: •Development of mechanistic absorption and distribution model for the FRT to predict tissue and fluid concentration after local and systemic exposure •Validation of predicted plasma, tissue and fluid concentrations for oral and intrauterine administration of levonorgestrel starting from a publicly available levonorgestrel model [1] •Implementation in the Open Systems Pharmacology (OSP) Suite [2] and open-source sharing frameworks Methods: A literature review was conducted to gather physiological data to inform model parameters such as specific blood flow and compartment volume for the organs of the FRT. The FRT model structure is implemented as a MoBi module V12 and can be used to extend any PB(P)K base model available in the OSP Suite. Levonorgestrel concentration-time profiles were simulated for blood plasma, uterine fluid, and cervical, vaginal, and uterine tissue after oral administration as well as for an intrauterine device (IUD). Patient data for plasma, myometrium, and endometrium concentration, collected from three studies available in the public domain, were used for the validation of the model predictions. Results: Four tissue compartments (cervix, vagina, endometrium, and myometrium) and two fluid compartments (uterine and cervicovaginal fluid) were informed using publicly available data. However, the ovaries and fallopian tubes were not included in the model due to the lack of tissue-specific data. Absorption and distribution parameters governing compound fate in the FRT are partly based on assumptions or numerical optimization. We investigated two options to describe drug release from an IUD (I) as a zero-order release process and (II) as a Weibull function. Both options were parametrized with in vivo release rate data spanning 8 years [3]. To correctly predict tissue concentrations in the endometrium and myometrium, the diffusion coefficient driving drug uptake from uterine fluid required optimization. The initial value (2.16E-7 cm2/min), derived from QSAR, was adjusted to approximately 27 times lower than the value estimated based on compound properties (8.03E-9 cm2/min). For the first study, the plasma concentrations were predicted with a 0.92-fold error on the area-under-the-curve (AUC) for the oral administration [1]. For IUD administration, the AUC was predicted within 0.87-fold error using a zero-order release process and within 0.63-fold error for Weibull function, respectively [4]. Despite the higher deviation on the AUC, a Weibull function improved the prediction of the concentration-time profile. Plasma and uterine tissue concentration predictions for oral and IUD levonorgestrel fall within the 2-fold deviation for the second study after introducing an additional parameter to account for differences in target availability. For oral administration, predicted tissue concentrations ( 8.09E-3 µmol/L and 0.01 µmol/L) were in line with the observed concentrations (4.00E-3 µmol/L and 0.01 µmol/L [5]) for myometrium and endometrium, respectively. Similarly for IUD administration, tissue concentrations (3.94E-3 µmol/L and 2.24 µmol/L) were predicted within 2-fold of the observed concentrations (7.77E-3 µmol/L and 2.48 µmol/L) for myometrium and endometrium, respectively. Conclusions: The presented model accurately predicts levonorgestrel plasma and tissue concentrations after oral and IUD administration. Only two minor parameter adjustments were necessary. To further validate the applicability of the FRT model structure, it is currently being tested for predicting the distribution of other medications, including treatments for infections and transmissible diseases. Hereafter, the validated structure will become available to the open-source community in the OPS Suite model library on GitHub. Overall, expanding the FRT model enables the prediction of tissue concentrations following both local and systemic drug administration. This capability is highly relevant for drug development in areas such as vaginal infections, protection against sexually transmitted diseases, and treatments for cervical and uterine cancer. Furthermore, the model has the potential to be integrated with QSP models for endocrine regulation or specific disease models, thereby broadening its applicability to drug development for female-specific health conditions. Lastly, the model could be a valuable in-silico tool for assessing the reproductive toxicity of compounds for regulatory risk assessments.
[1] Cicali, Brian, et al. “Quantitative assessment of levonorgestrel binding partner interplay and drug-drug interactions using physiologically based pharmacokinetic modeling.” CPT: Pharmacometrics & Systems Pharmacology 10.1 (2021): 48-58. [2] Lippert, Jörg, et al. “Open systems pharmacology community—an open access, open source, open science approach to modeling and simulation in pharmaceutical sciences.” CPT: pharmacometrics & systems pharmacology 8.12 (2019): 878.1 [3] https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021225s019lbl.pdf [4] Apter, Dan, et al. “Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies.” Fertility and Sterility 101.6 (2014): 1656-1662. [5] Nilsson, C. G., et al. “Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD.” Clinical endocrinology 17.6 (1982): 529-536.
Reference: PAGE 33 (2025) Abstr 11589 [www.page-meeting.org/?abstract=11589]
Poster: Drug/Disease Modelling - Other Topics