Pharmacokinetics of tenofovir monoester and association with intracellular tenofovir diphosphate following single-dose tenofovir disoproxil fumarate

Abstract

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® 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) Tmax of 0.5 h (0.25-2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0-4 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 AUC0-∞ (but not tenofovir AUC0-∞) 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 Cmax and AUC0-4 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.

Figure 1.

Structures of tenofovir disoproxil, tenofovir monoester, and tenofovir. Figure adapted from Murphy RA, Valentovic MA. Factors contributing to the antiviral effectiveness of tenofovir. J Pharmacol Exp Ther 2017; 363: 156–163, by permission of The American Society for Pharmacology and Experimental Therapeutics.

Figure 2.

(a) Mean ± SD plasma concentrations of tenofovir monoester (filled circles) and tenofovir (TFV; open circles) until 4 h post-dose. (b) Tenofovir versus tenofovir monoester AUC_0–4 in plasma. Tenofovir AUC_0–4 was ln transformed prior to analysis for comparison with tenofovir monoester (original scale). Data are presented as line of best fit with 95% CI indicated by the dotted lines.

Figure 3.

Observed versus predicted plots of tenofovir diphosphate concentrations in PBMC with (a) tenofovir monoester and (b) tenofovir, and tenofovir diphosphate concentrations in DBS with (c) tenofovir monoester and (d) tenofovir. Data are presented as percentage change (95% CI). Filled circles indicate data points from visit 1. Open circles indicate data points from visit 2. Solid lines indicate predictions from all visits in PBMC and visit 1 in DBS, and dashed lines indicate predictions from visit 2.