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

Brooks, Kristina M; Ibrahim, Mustafa; Castillo‐Mancilla, José; MaWhinney, Samantha; Alexander, Keisha; Tilden, Scott; Kerr, Becky Jo; Ellison, Lucas; McHugh, Cricket; Bushman, Lane R.; Kiser, Jennifer J.; Hosek, Sybil; Huhn, Gregory; Anderson, Peter L.

doi:10.1093/jac/dkz187

Cited by 12 publications

(9 citation statements)

References 35 publications

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“…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.…”

Section: Resultsmentioning

confidence: 61%

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

SILVA

Moreira

Vasconcelos

et al. 2022

Preprint

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Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug extensively used by people living with HIV/AIDS. TDF molecule is hydrolysed in vivo and liberate the tenofovir, the active part of the molecule. Tenofovir is a very stable drug and the discharge of its residues into the environment can potentially lead to risk for aquatic species. This study evaluated the TDF biodegradation and removal by cultures of Microcystis novacekii, non axenic, it presented the bacteria Pseudomonas pseudoalcaligenes associated. Concentrations of TDF 12.5, 25.0 and 50.0 mg.L-1 were used to the tests. The process occurred in two stages. In the first 72 hours, TDF was de-esterified, forming the tenofovir monoester intermediate by abiotic and enzymatic process associated in extra cell medium. In a second step, the monoester was removed from the culture medium by intracellular processes. At the end of the experiment 88.7 to 94.1% of TDF and its monoester derivative were removed from the culture medium over 16 days. This process showed higher efficiency to the TDF removal at the concentration 25 mg.L-1. The tenofovir or others by-products of TDF were not observed in the test conditions. Tenofovir isoproxil monoester has partial antiviral activity and has shown to be persistent, maintaining a residual concentration after 16 days, indicating the need to continue the research on methods of this product total removal from the aquatic environment.

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Section: Resultsmentioning

confidence: 61%

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

SILVA

Moreira

Vasconcelos

et al. 2022

Preprint

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“…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.…”

Section: Discussionmentioning

confidence: 79%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Brooks

Castillo‐Mancilla

Blum

et al. 2019

Journal of Antimicrobial Chemotherapy

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BackgroundIntracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.MethodsHIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.ResultsTen participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0–287.5) and 0.74 ng/mL (0.27–2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40–18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25–11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71–4.57; P = 0.001) and 7.31-fold (95% CI 4.47–11.95; P < 0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir.ConclusionsTenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Garcia

Rad

Saeedinejad

et al. 2022

Nanomedicine (Lond.)

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Background: Combination antiretroviral therapy has significantly advanced HIV-1 infection treatment. However, HIV-1 remains persistent in the brain; the inaccessibility of the blood–brain barrier allows for persistent HIV-1 infections and neuroinflammation. Nanotechnology-based drug carriers such as nanodiscoidal bicelles can provide a solution to combat this challenge. Methods: This study investigated the safety and extended release of a combination antiretroviral therapy drug (tenofovir)-loaded nanodiscs for HIV-1 treatment in the brain both in vitro and in vivo. Result: The nanodiscs entrapped the drug in their interior hydrophobic core and released the payload at the desired location and in a controlled release pattern. The study also included a comparative pharmacokinetic analysis of nanodisc formulations in in vitro and in vivo models. Conclusion: The study provides potential applications of nanodiscs for HIV-1 therapy development.

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

Cited by 12 publications

References 35 publications

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

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

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

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

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