Pharmacology and Molecular Sciences and Clinical Pharmacology, Johns Hopkins School of Medicine
Pharmacogenomic Determinants of Tenofovir and Tenofovir-Diphosphate Exposure
Tenofovir (TFV) is a nucleotide analogue HIV reverse transcriptase inhibitor that is used for HIV pre-exposure prophylaxis (PrEP); however, inter-individual variability in the levels of the active phosphorylated anabolite of TFV, TFV-diphosphate (TFV-DP), following either oral or topical dosing of TFV has been reported. In addition, following oral dosing of TFV the levels of TFV-DP in rectal tissue are markedly higher than those in vaginal tissue. The mechanism(s) underlying these phenomena have yet to be defined. The proposed studies will test the hypothesis that tissue specific expression levels and genetic polymorphisms of intracellular kinases and/or drug transporters underlie the differential tissue concentrations and inter-individual variability in the pharmacokinetics and pharmacodynamics of TFV. To address this, we will take an integrative approach using state-of-the-art molecular and biochemical techniques. Interestingly, we have already identified an isoform of deoxycytidine kinase (an enzyme demonstrated to be involved in TFV phosphorylation) that is expressed in vaginal and rectal tissue but not in liver indicating that there may be a difference in phosphorylation of TFV when administered orally versus topically. Our proposed studies will include genotyping of samples collected from the Microbicide Trials Network (MTN)-001 study. MTN-001 employed a cross-over design in which participants received daily doses of oral tenofovir disoproxil fumarate (TDF), 1% TFV vaginal gel or both for 6 weeks in randomized sequence. Completion of this work may inform the optimization of the administration of drugs used in HIV PrEP in mucosal tissues while also having a broader impact on gynecological and gastrointestinal pharmacology.