Pharmacokinetics of Tenofovir Monoester and Association with Intracellular Tenofovir Diphosphate Following Single-Dose Tenofovir Disoproxil Fumarate

Background: Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. Methods: Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus (R) ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. Results: Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) T-max of 0.5 h (0.25-2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t(1/2) of 26 min (31.0%). Tenofovir monoester C-max was 131.6 ng/mL (69.8%) and AUC(0-4) was 93.3 ng.h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng.h/mL (30.0%). Tenofovir monoester AUC(0-infinity) (but not tenofovir AUC(0-infinity)) was a significant predictor of tenofovir diphosphate in both PBMC (P=0.015) and DBS (P=0.005), increasing by 3.8% (95% CI 0.8%-6.8%) and 4.3% (95% CI 1.5%-7.2%), respectively, for every 10 ng.h/mL increase in tenofovir monoester. Conclusions: Tenofovir monoester C-max and AUC(0-4) were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.