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Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues.

ABSTRACT: Objectives:Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues. Methods:Healthy seronegative women were given 5, 10 or 25?mg of tenofovir alafenamide ( n? = ? 8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57-1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10??M tenofovir alafenamide or tenofovir. clinicaltrials.gov: NCT02357602. Results:Following single doses of 5, 10 and 25?mg, median (IQR) tenofovir plasma AUC 0-14?days was 52.8 (49.5-59.6), 78.1 (68.2-86.9) and 169.7 (131.2-211.4) ng·h/mL and tenofovir-dp PBMC AUC 0-14?days was 2268 (1519-4090), 4584 (3113-5734) and 9306 (6891-10785) fmol·h/10 6 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI?=?0.87-1.15 and 0.62-1.02, respectively). In vitro tenofovir-dp was 1.7-17-fold higher in epithelial cells than PBMCs. Conclusions:After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology.

SUBMITTER: Cottrell ML

PROVIDER: S-EPMC5536328 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues.

Cottrell Mackenzie L ML Garrett Katy L KL Prince Heather M A HMA Sykes Craig C Schauer Amanda A Emerson Cindi W CW Peery Anne A Rooney James F JF McCallister Scott S Gay Cynthia C Kashuba Angela D M ADM

The Journal of antimicrobial chemotherapy 20170601 6

<h4>Objectives</h4>Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues.<h4>Methods</h4>Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide ( n = 8/ ...[more]

PMID: 28369415

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Project description:Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

Project description:Recent data support that the vaginal microbiota may alter mucosal pharmacokinetics (PK) of topically delivered microbicides. Our team developed an intravaginal ring (IVR) that delivers tenofovir (TFV) (8-10 mg/day) alone or with levonorgestrel (LNG) (20 ug/day). We evaluated the effect of IVRs on the vaginal microbiota, and describe how the vaginal microbiota impacts mucosal PK of TFV. CONRAD A13-128 was a randomized, placebo controlled phase I study. We randomized 51 women to TFV, TFV/LNG or placebo IVR. We assessed the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and after approximately 15 days of use. We measured the concentration of TFV in the cervicovaginal (CV) aspirate, and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue at the end of IVR use. The change in relative or absolute abundance of vaginal bacterial phylotypes was similar among active and placebo IVR users (all q values >0.13). TFV concentrations in CV aspirate and vaginal tissue, and TFV-DP concentrations in vaginal tissue were not significantly different among users with community state type (CST) 4 versus those with Lactobacillus dominated microbiota (all p values >0.07). The proportions of participants with CV aspirate concentrations of TFV >200,000 ng/mL and those with tissue TFV-DP concentrations >1,000 fmol/mg were similar among women with anaerobe versus Lactobacillus dominated microbiota (p = 0.43, 0.95 respectively). There were no significant correlations between the CV aspirate concentration of TFV and the relative abundances of Gardnerella vaginalis or Prevotella species. Tissue concentrations of TFV-DP did not correlate with any the relative abundances of any species, including Gardnerella vaginalis. In conclusion, active IVRs did not differ from the placebo IVR on the effect on the vaginal microbiota. Local TFV and TFV-DP concentrations were high and similar among IVR users with Lactobacillus dominated microbiota versus CST IV vaginal microbiota. Trial registration: ClinicalTrials.gov NCT02235662.

Project description:Background: HIV pre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine is effective when taken daily. Previously, we developed a urine assay capable of detecting the prodrug tenofovir (TFV) in patients taking tenofovir disoproxil fumarate (TDF)-based PrEP. However, tenofovir alafenamide (TAF) has replaced TDF due to its different safety profile for HIV treatment and was recently approved as PrEP. Given the need to ensure the aforementioned assay remains available for the purpose of objective adherence monitoring, it is critical to ensure its accuracy for detecting TFV in patients taking TAF. Methods: Blood and urine samples were collected from 3 cohorts of patients: (1) 10 participants living with HIV (PLWH) with suppressed virus on a TAF-based regimen, (2) 10 HIV-participants administered 1 dose of TAF/FTC followed by urine and plasma sampling for 7 days starting 1-3 h post-dose, and (3) 10 HIV-participants administered 7 doses of TAF/FTC followed by urine and plasma sampling for 10 days starting 1-3 h after the last dose. Samples were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with high sensitivity and specificity for TFV. HIV-samples were compared to a historical cohort administered one dose of TDF/FTC. Results: PLWH were 90% male, 40% African American, and 10% Hispanic (mean age = 57 y; SD 8.88 y). HIV-participants were 55% male and 70% Caucasian (mean age = 31.6 y; SD 7.70 y). Samples from PLWH demonstrated TFV concentrations 2 logs higher in urine than plasma (1,000 ng/mL vs ±10 ng/mL) at the time of collection. Urine samples following a single dose of TAF in HIV-participants yielded TFV concentrations ranging from 100 to 1,000 ng/mL 1-3 h post-dose and remained >100 ng/mL for 6 days in 8 of 10 participants. Urine samples collected after 7 consecutive doses of TAF yielded TFV concentrations >1,000 ng/mL 1-3 h after dosing discontinuation, with TFV concentrations >1,00 ng/mL 7 days post discontinuation in 8 of 10 participants. Urine TFV concentrations following TAF administration were comparable to those from a historical cohort administered TDF/FTC. Plasma TFV concentrations were low(±10 ng/mL) in both HIV-cohorts at all time points. Conclusions: TFV persists in urine at detectable concentrations in participants taking TAF/FTC for at least 7 days despite largely undetectable plasma concentrations, with urine TFV concentrations comparable to patients taking TDF/FTC. This study demonstrates the ability of a urine TFV assay to measure recent TAF adherence.

Dataset Information

Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues.

Publications

Single-dose pharmacokinetics of tenofovir alafenamide and its active metabolite in the mucosal tissues.

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