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 dosing period, sustained release or “long-acting” ARV formulations hold significant promise for increasing the effectiveness of HIV-1 pre-exposure 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 d^-1 in vitro was evaluated in beagle dogs over 40 d 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, IQR 0.60-1.50 ng ml^-1) and tenofovir (TFV, median 15.0 ng ml^-1, IQR 8.8-23.3 ng ml^-1), the product of in vivo TAF hydrolysis. High concentrations (median 512 fmol/10⁶ cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells, 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 successful proof-of-principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.