Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis

Abstract

Oral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day(-1) in vitro was evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml(-1); interquartile range [IQR], 0.60 to 1.50 ng ml(-1)) and tenofovir (TFV; median, 15.0 ng ml(-1); IQR, 8.8 to 23.3 ng ml(-1)), the product of in vivo TAF hydrolysis. High concentrations (median, 512 fmol/10(6) cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.

FIG 1

Three-dimensional model (A) and cross-sectional drawings (B and C) of TAF implant. The TAF core (black) inside the silicone scaffold with PVA membrane coating is shown (not to scale). Cross sections were sliced through the y-z (B) and x-y planes (C).

FIG 2

TAF LA displays pseudo-zero-order (linear) cumulative in vitro release kinetics (means, n = 6). The solid line corresponds to linear regression (R² = 0.8231) between 4 and 30 days, resulting in a TAF release rate of 0.92 ± 0.031 mg day⁻¹.

FIG 3

Subdermal implantation of TAF LA prototype device in beagle dogs maintains sustained drug levels with low systemic exposure to TAF and TFV with concomitant, efficient PBMC loading with TFV-DP. Pharmacokinetic profiles of plasma TAF (closed circles) and TFV (open circles) and PBMC TFV-DP (closed diamonds). Each data point represents the means ± standard deviations from four beagle dogs, and dotted lines correspond to the median concentrations for each analyte over the 40-day study. Note that TFV-DP levels were measured only after day 20.

FIG 4

Molar TAF:TFV plasma concentration ratios are stable throughout the 40-day study. Each data point represents the means ± standard deviations from four beagle dogs.

FIG 5

Simulation of TAF pharmacokinetics in beagle dogs based on in vitro implant release rates. (A) Graphical model. C, simulated plasma TAF concentration; V, volume of distribution (6.8 liters); Cl, clearance (473 liters day⁻¹); A0, amount of drug cleared; A1, amount in the central compartment 1; CObs, observed plasma TAF concentration; S1 Rate, zero-order release rate from implant (1.9 μmol day⁻¹, 0.92 mg day⁻¹). (B) Actual individual (closed circles) and simulated (dotted line) TAF plasma levels. The dose was 90 μmol (43 mg), and the bioavailability (F) of the implant was assumed to be 100%. Note the linear y axis.