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Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation.

ABSTRACT: Pharmacokinetic (PK) data describing a prolonged time course of antiretrovirals in plasma and peripheral blood mononuclear cells (PBMCs) are important for understanding and managing late or missed doses and to assess the appropriateness of compounds for preexposure prophylaxis (PrEP). This study aimed to evaluate the PK of coformulated tenofovir disoproxil fumarate (DF), emtricitabine, and rilpivirine in plasma and of the intracellular (IC) anabolites tenofovir diphosphate (TFV-DP) and emtricitabine triphosphate (FTC-TP) in healthy volunteers up to 9 days after drug cessation. Individuals received daily tenofovir DF-emtricitabine-rilpivirine (245/200/25 mg) for 14 days. Drug intake was stopped, and serial sampling occurred prior to the final dose and up to 216 h (9 days) after stopping drug intake. Concentrations were quantified and PK parameters calculated. Eighteen volunteers completed the study. The terminal elimination plasma half-lives for tenofovir and emtricitabine over 216 h (geometric mean [90% confidence interval]) were higher than those seen over 0 to 24 h (for tenofovir, 31 h [27 to 40 h] versus 13.3 h [12.5 to 15.1 h]; for emtricitabine, 41 h [36 to 54 h] versus 6.4 h (5.9 to 7.6 h]). Model-predicted IC half-lives (0 to 168 h) were 116 h (TFV-DP) and 37 h (FTC-TP). The plasma rilpivirine concentration at 216 h was 4.5 ng/ml (4.2 to 6.2 ng/ml), and half-lives over 0 to 216 h and 0 to 24 h were 47 h (41 to 59 h) and 35 h (28 to 46 h), respectively. These data contribute to our understanding of drug behavior following treatment interruption; however, adherence to therapy should be promoted. Validated plasma and IC target concentrations are necessary to allow interpretation with respect to sustained virus suppression or HIV prevention. (The trial was conducted in accordance with the Declaration of Helsinki [EudraCT 2012-002781-13].).

SUBMITTER: Dickinson L

PROVIDER: S-EPMC4576083 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation.

Dickinson Laura L Yapa H Manisha HM Jackson Akil A Moyle Graeme G Else Laura L Amara Alieu A Khoo Saye S Back David D Karolia Zeenat Z Higgs Chris C Boffito Marta M

Antimicrobial agents and chemotherapy 20150720 10

Pharmacokinetic (PK) data describing a prolonged time course of antiretrovirals in plasma and peripheral blood mononuclear cells (PBMCs) are important for understanding and managing late or missed doses and to assess the appropriateness of compounds for preexposure prophylaxis (PrEP). This study aimed to evaluate the PK of coformulated tenofovir disoproxil fumarate (DF), emtricitabine, and rilpivirine in plasma and of the intracellular (IC) anabolites tenofovir diphosphate (TFV-DP) and emtricita ...[more]

PMID: 26195515

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Project description:BackgroundTranswomen have an increased risk of HIV acquisition compared with other adults. Drug-drug interactions between pre-exposure prophylaxis (PrEP) and gender-affirming therapy are cited as a reason for poor PrEP uptake among transwomen. We evaluated plasma tenofovir and emtricitabine pharmacokinetics and their active intracellular anabolites, tenofovir-diphosphate and emtricitabine-triphosphate, in transwomen receiving feminizing hormones.MethodsWe enrolled HIV-negative transwomen (≥19 years) not receiving PrEP. Participants took oral tenofovir disoproxil fumarate/emtricitabine 300/200 mg daily for 14 days. Plasma was collected at 0 h (pre-dose), 0.5, 1, 2, 3, 4, 6, 8 and 12 h on day 14 post-tenofovir disoproxil fumarate/emtricitabine dose. The plasma AUC0-24 was calculated using the trapezoidal rule and compared with historical HIV-negative cisgender adults as geometric mean ratios (GMRs, 90% CI). Secondarily, tenofovir-diphosphate and emtricitabine-triphosphate from PBMCs collected at 0 h and 12 h were reported descriptively as geometric means (90% CI). Clinical trials registration: NCT03270969.ResultsAmong 15 transwomen (mean age 32 years), geometric mean tenofovir and emtricitabine plasma AUC0-24 were lower compared with controls: tenofovir, 2.10 versus 2.76 mg·h/L, GMR 0.76 (0.65-0.90), P = 0.01; emtricitabine, 9.15 versus 10.64 mg·h/L, GMR 0.86 (0.75-0.98), P = 0.07. Tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in the literature: 167.1 (146.6-190.5) fmol/106 cells and 15.4 (13.8-17.3) pmol/106 cells, respectively.ConclusionsWe observed lower plasma tenofovir and emtricitabine concentrations in transwomen compared with historical cisgender adults, yet intracellular tenofovir-diphosphate and emtricitabine-triphosphate concentrations were higher than previously reported in PBMCs. Understanding the differences of PrEP pharmacokinetics in plasma and tissue compartments and the resultant impact on efficacy remains important for transwomen.

Project description:The coformulation of the nucleos(t)ide analogs (NA) tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC) is approved for HIV-infection treatment and prevention. Plasma TFV and FTC undergo complicated hybrid processes to form, accumulate, and retain as their active intracellular anabolites: TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP). Such complexities manifest in nonlinear intracellular pharmacokinetics (PK). In target cells, TFV-DP/FTC-TP compete with endogenous deoxynucleoside triphosphates (dNTP) at the active site of HIV reverse transcriptase, underscoring the importance of analog:dNTP ratios for antiviral efficacy. However, NA such as TFV and FTC have the potential to disturb the dNTP pool, which could augment or reduce their efficacies. We conducted a pharmacokinetics-pharmacodynamics (PKPD) study among forty subjects receiving daily TDF/FTC (300 mg/200 mg) from the first-dose to pharmacological intracellular steady-state (30 days). TFV/FTC in plasma, TFV-DP/FTC-TP and dNTPs in peripheral blood mononuclear cells (PBMC) were quantified using validated LC/MS/MS methodologies. Concentration-time data were analyzed using nonlinear mixed effects modeling (NONMEM). Formations and the accumulation of intracellular TFV-DP/FTC-TP was driven by plasma TFV/FTC, which was described by a hybrid of first-order formation and saturation. An indirect response link model described the interplay between TFV-DP/FTC-TP and the dNTP pool change. The EC50 (interindividual variability, (%CV)) of TFV-DP and FTC-TP on the inhibition of deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) production were 1020 fmol/106 cells (130%) and 44.4 pmol/106 cells (82.5%), resulting in (90% prediction interval) 11% (0.45%, 53%) and 14% (2.6%, 35%) reductions. Model simulations of analog:dNTP molar ratios using IPERGAY dosing suggested that FTC significantly contributes to the protective effect of preexposure prophylaxis (PrEP). Simulation-based intracellular operational multiple dosing half-lives of TFV-DP and FTC-TP were 6.7 days and 33 hours. This model described the formation of intracellular TFV-DP/FTC-TP and the interaction with dNTPs, and can be used to simulate analog:dNTP time course for various dosing strategies.

Dataset Information

Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation.

Publications

Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation.

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