Population pharmacokinetics of tenofovir alafenamide delivered via an annual subdermal implant in South African women

A diverse portfolio of HIV prevention products likely will be needed to help attain the ambitious targets set by UNAIDS for the global reduction in HIV incidence. Ultralong-acting systemic drug regimens with dosing frequencies of one year or longer represent a promising strategy for HIV-1 pre-exposure prophylaxis (PrEP) as they hold the potential of being discreet and overcoming some of the adherence burden associated with daily oral drug dosing. We have developed an innovative subdermal implant delivering the potent antiretroviral prodrug tenofovir alafenamide (TAF) evaluated in CAPRISA 018, a first-in-human, randomized, placebo-controlled clinical trial in South African women. Population PK modeling was used to present an in-depth analysis of the CAPRISA 018 results. A literature model was adapted and applied to predict plasma TAF and tenofovir (TFV) concentrations, as well as peripheral blood mononuclear cell (PBMC) TFV diphosphate (TFV-DP) concentrations that agreed with measured values. A Weibull model was used to calculate the in vivo TAF release kinetics based on plasma TAF concentrations. While the release profiles were variable, at least half the implants (57%) displayed linear in vivo TAF release profiles. The relationship between implant TAF release rates and PBMC TFV-DP concentrations informed targets for future studies (0.39–1.4 mg d-1, depending on the selected prophylactic TFV-DP concentration) assuming the local tolerability issues can be overcome, fulfilling a key objective of the CAPRISA 018 trial.