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.

Biodegradation of the antiviral tenofovir disoproxyl by a cyanobacteria/bacteria culture.

“…Even with the good results obtained in this study, it should be noted that tenofovir is an inhibitor of DNA synthesis, and its metabolite TMF is partially active (Brooks et al 2019), its persistence in the environment can potentially lead to damage to the genetic heritage of exposed species. Thus, the persistence of TMF in the culture medium for more than 15 days is worrying and points to the need for further studies on the biodegradation of this antiviral in order to prevent possible genotoxic actions to other aquatic organisms.…”

Increased tenofovir monoester concentrations in patients receiving tenofovir disoproxil fumarate with ledipasvir/sofosbuvir

“…Initial studies on the pharmacology of TDF reported its conversion to tenofovir as rapid and spontaneous, resulting in no detectable tenofovir monoester in plasma. 9 However, in conjunction with the analyses published in this article, Brooks et al 11 demonstrated tenofovir monoester exhibits quantifiable pharmacokinetics in vivo following a single TDF/emtricitabine dose. Baseline tenofovir monoester concentrations in this study were higher than those quantified in the healthy volunteer study at 1 and 4 h post-dose, where geometric mean concentrations at the same timepoints were 39 ng/mL and 0.17 ng/mL, respectively.…”

“…28 There are limitations to this study. First, a limited sampling strategy was used as the original focus of the study was to measure changes in plasma tenofovir concentrations, but tenofovir monoester peaks at 0.5 h post-dose and has a t1 =2 of 0.44 h. 11 Thus, true peak concentrations of tenofovir monoester were likely missed and AUC calculations were not possible. Additionally, this was a small sample size and two different participants had low tenofovir monoester concentrations at 1 h post-dose compared with the rest of the study participants, one at baseline and the other 4 weeks after initiating ledipasvir/sofosbuvir.…”

“…Tenofovir monoester in plasma was quantified using a novel UPLC-MS method. 11 This method was linear over a range of 0.1 to 500 ng/mL using a 1/concentration 2 weighted calibration curve. Samples exceeding the upper limit of quantification were diluted and reanalysed.…”

Effect of Drug-To-Lipid Ratio on Nanodisc-Based Tenofovir Drug Delivery to The Brain for HIV-1 Infection

“…TFV is known to have poor permeation/penetration across the cell. However, once inside the cells, TFV converts to a diphosphate form that stays inside the cell for a long time due to its charged nature [ 68 , 69 ]. Administering TFV as the ND formulation may improve therapeutic outcomes in HIV-1 infection.…”