A Pharmacokinetic/Pharmacodynamic Model to Predict Effective HIV Prophylaxis Dosing Strategies for People Who Inject Drugs.

Autor: Garrett KL; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Chen J; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Maas BM; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Cottrell ML; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Prince HA; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Sykes C; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Schauer AP; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., White N; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Dumond JB; Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy (K.L.G., J.C., B.M.M., M.L.C., C.S., A.P.S., J.B.D.), and School of Medicine (H.A.P., N.W.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina jdumond@unc.edu.
Jazyk: angličtina
Zdroj: The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2018 Nov; Vol. 367 (2), pp. 245-251. Date of Electronic Publication: 2018 Aug 27.
DOI: 10.1124/jpet.118.251009
Abstrakt: The goal of this work was to evaluate dosing strategies for tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine (FTC) for pre-exposure prophylaxis (PrEP) with injection drug use with a pharmacokinetic/pharmacodynamics analysis of concentration data generated from two single-dose clinical studies conducted in healthy women. Population pharmacokinetic models were developed using measured intracellular metabolite, endogenous nucleotide competitors, and extracellular parent drug concentrations. Intracellular metabolite concentrations were normalized to endogenous competitors and compared with an EC 90 target for PrEP efficacy. Monte Carlo simulations were used to select effective dose strategies of single agents (TAF, TDF, and FTC) and combinations (TDF + FTC and TAF + FTC). Daily, intermittent, and event-driven dosing regimens at varying dosage amounts were explored. When combined, TDF + FTC and TAF + FTC both provided quick (0.5 hours) and durable (up to 84 and 108 hours, respectively) protection of ≥99% after a single dose. When dosed twice per week, protection remained at 100%. Single-agent regimens provided lower estimates of protection than either combination tested. Here, the application of pharmacokinetic modeling to in vitro target concentrations demonstrates the added utility of including FTC in a successful PrEP regimen. While no TAF-based PrEP data are currently available for comparison, this analysis suggests TAF + FTC could completely protect against percutaneous exposure with as little as two doses per week.
(Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze: MEDLINE
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