SUMMARY The proposed project aims to increase our knowledge regarding the intersection of pharmacogenomics, contraceptive efficacy, and health disparities. U.S. women of color are at much greater risk of experiencing contraceptive failure, resulting in more unintended pregnancies than their white peers. While social determinants of health, such as racial discrimination and access to healthcare, contribute meaningfully to contraceptive availability and use, inherent pharmacogenomic differences could also account for significant individual-to-individual disparities in efficacy. The most effective oral emergency contraceptive (EC) method, ulipristal acetate (UPA), which works by blocking progesterone action in the preovulatory follicle, appears to be less effective in certain populations even when optimally dosed. We have demonstrated that UPA is converted to inactive metabolites by the enzyme cytochrome P450 3A5 (CYP3A5). Moreover, we established that the primate ovarian follicle, the site of UPA action as an EC, expresses remarkably high levels of CYP3A5 through the periovulatory interval and luteal development. The genotype and phenotype frequency of an active variant of CYP3A5 is significantly greater in those identifying as Black as compared to whites, with the latter possessing primarily a nonfunctional variant. Because active CYP3A5 is a major contributor to drug metabolism, we hypothesize that UPA is significantly less effective at preventing ovulation in women with the active CYP3A5 variant. In this proposal, we will determine if follicular CYP3A5 reduces intraovarian UPA levels relative to what is observed systemically (Aim 1) using the clinically relevant rhesus macaque model. Studies will also be performed to determine if blocking CYP3A5 activity leads to greater UPA efficacy in inhibiting processes essential for ovulation. In complementary human subjects studies, we plan to assess if CYP3A5 genotype (active versus inactive form) determines UPA efficacy (Aim 2). Women recruited for this study will be genotyped and categorized as possessing active or inactive CYP3A5 alleles and then assessed for UPA pharmacodynamics. We will also explore other genetic variants that might play a role in drug metabolism. The primary endpoint includes determining if significant differences exist in the rate at which UPA fails to prevent ovulation and the pharmacokinetics of UPA metabolism related to the CYP3A5 genotype. The results of the studies will determine if a genetic predisposition exists for racial disparities in contraceptive efficacy and the risk for unintended pregnancy. The broad, long-term goal of this research includes providing a means to maximize the therapeutic potential of UPA in women through testing to identify individuals at risk for failure and/or developing approaches to limit drug metabolism.