Mechanism-Based Predictions of Local Tissue and Systemic Exposure for Drug Products Delivered Through the Female...

Effective drug delivery through the female reproductive tract (FRT) presents unique challenges due to the lack of robust predictive models for drug exposure via this route. Addressing this gap, we developed and evaluated a comprehensive whole-body physiologically based pharmacokinetic (PBPK) model that incorporates anatomical and physiological information of the FRT. This model was calibrated using both published and experimental data for the drug levonorgestrel (LNG), administered via oral, vaginal, and intrauterine routes. The PBPK model simulates drug absorption, distribution, and elimination, providing predictions of local tissue concentrations and systemic exposure. The majority of observations can be contained within or overlaid with the simulated profiles. Noteworthy is the model's capability to predict the pharmacokinetics of LNG with reasonable precision across different administration routes, thereby demonstrating its potential utility in supporting drug development and regulatory decisions. The application of this model allows for exploration of drug formulations and dosing regimens, reducing the reliance on extensive clinical trials. Furthermore, the model may potentially be used to facilitate generic drug development, and thus promote generic competition, for drug products that are important in women's health. By bridging critical knowledge gaps, this model facilitates in silico evaluation of drugs administered through the FRT, potentially fostering advancements in therapeutic strategies and patient care.