Lack of clinically important PK interaction between coformulated ledipasvir/sofosbuvir and rilpivirine/emtricitabine/tenofovir alafenamide

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 [ C max ] and area under the concentration versus time curve over the dosing interval [ AUC tau ] for ledipasvir, sofosbuvir, and the metabolites GS ‐566500 and GS ‐331007. Ledipasvir/sofosbuvir had no effect on the C max and AUC tau for rilpivirine and emtricitabine. The C max and AUC tau 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.