The drug-drug interaction (DDI) potential between the fixed-dose combinations of ledipasvir/sofosbuvir 90/400 mg for hepatitis C virus and emtricitabine/rilpivirine/tenofovir alafenamide (TAF) 200/25/25 mg for HIV was evaluated in a randomized, open-label, single-center, multiple-dose, 3-way, 6-sequence, crossover Phase 1 study in 42 healthy subjects. Emtricitabine/rilpivirine/TAF had no relevant effect on the pharmacokinetic parameters of maximum concentration [Cmax ] and area under the concentration versus time curve over the dosing interval [AUCtau ] for ledipasvir, sofosbuvir, and the metabolites GS-566500 and GS-331007. Ledipasvir/sofosbuvir had no effect on the Cmax and AUCtau for rilpivirine and emtricitabine. The Cmax and AUCtau of tenofovir, the major metabolite of TAF, were increased by 62% and 75%, respectively. However, the resulting absolute tenofovir exposures were markedly lower than the historical tenofovir exposures following tenofovir disoproxil fumarate (TDF) and, as such, were not considered to be clinically relevant. In contrast, additional adverse effect monitoring is recommended upon coadministration of ledipasvir and TDF due to elevated tenofovir exposures resulting from the DDI. This difference is explained by the fact that TAF 25 mg results in markedly lower (~90%) plasma tenofovir exposure compared to TDF 300 mg. Ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF were generally well tolerated when administered alone or in combination. HIV/hepatitis C virus-coinfected patients can coadminister ledipasvir/sofosbuvir and emtricitabine/rilpivirine/TAF without dosage adjustments.
Keywords: HCV; HIV; Coinfection; drug interaction; ledipasvir; pharmacokinetics; rilpivirine; sofosbuvir; tenofovir alafenamide.
© 2017 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.