PT-002 - DETERMINING CRITICAL PHYSIOLOGICAL AND DRUG SPECIFIC PARAMETERS FOR ENHANCING A PHYSIOLOGICALLY-BASED PHARMACOKINETICS MODEL FOR THE FEMALE REPRODUCTIVE TRACT

A. Le¹, P. Graebing¹, L. Wang¹, J. Zhang¹, R. Bies², L. Rohan¹; ¹University of Pittsburgh, Pittsburgh, PA, United States, ²University of Buffalo, Buffalo, NY, United States.

Background: Currently, there is a lack of drug exposure data within the female reproductive tract (FRT) including the fallopian tubes, and across different administration routes. Knowledge regarding gene expression of drug metabolizing enzymes and transporters in the FRT is also limited. These deficiencies pose a significant challenge in the drug discovery and development. This work aimed to gain a better understanding of the biodistribution to accurately predict drug exposures within the FRT. Our group has previously established a PBPK model tailored for the FRT including the vaginal, cervical, and uterine compartments using data obtained for several antiviral and contraceptive drugs.

Methods: To further refine and validate our PBPK model, we characterized physiological and drug-specific parameters using a panel of model drugs with diverse physicochemical properties and extended the model to include the fallopian tubes. In this study, tissue homogenates (uterus and cervix) and biological fluids (plasma and cervicovaginal fluid) protein binding was conducted using rapid equilibrium dialysis device followed by LC-MS/MS quantitation. Gene expression of 12 drug transporters and 21 phase I and II drug metabolizing enzymes within the FRT were quantified from 6 donors each using qPCR.

Results: As anticipated, highly hydrophobic drugs were found to have high protein binding in human biological fluids and tissue homogenates. Fallopian tubes showed relatively high expression of efflux transporters (with > 50% of expression compared to that of the liver) in 3 out of the 6 transporters. These transporters include ABCB1/P-gp, ABCG2/BCRP, and ABCC4/MRP4 (ABCB1 12.8-fold > liver, ABCG2 7.0-fold > liver, ABCC4 5.9-fold> liver all p-value < 0.05). The uptake transporters in fallopian tubes had similar expression levels across all six donors. Immunohistochemistry analysis localized these efflux transporters to the mucosal folds. Across all donors, 15 phase I and II drug metabolizing enzymes were consistently expressed in all fallopian tubes and uterine samples.

Conclusion: The data generated in this study will help enhance the established PBPK model, enabling a more precise comprehension and prediction of drug distribution and exposure in the FRT to support the drug discovery and development.