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

Abstract

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.

HIV/HCV therapy with ledipasvir/sofosbuvir after randomized switch to emtricitabine-tenofovir alafenamide-based single-tablet regimens

“…https://doi.org/10.1371/journal.pone.0224875.g003 combined with either E/C/F/TAF or R/F/TAF regimens. Furthermore, this study confirmed pharmacokinetic data in healthy volunteers showing no clinical risk of renal toxicity when either boosted (E/C/F/TAF) or unboosted (R/F/TAF) TAF-based regimens were co-administered with 12 weeks of LDV/SOF [21]; there were minimal changes seen in eGFR CG and improvements in urinary protein markers for participants receiving both regimens.…”

“…Since tenofovir alafenamide (TAF) has 80-91% lower plasma TFV concentrations than TDF, the renal safety of concomitant treatment with LDV/SOF may be improved with TAF compared to TDFbased regimens [20]. Two phase 1 studies in healthy participants evaluated DDIs between LDV/SOF and two F/TAF-based antiretroviral therapy (ART) regimens: rilpivirine/emtricitabine/TAF (R/F/TAF) or elvitegravir/cobicistat/emtricitabine/TAF (E/C/F/TAF) [21,22]. LDV/SOF co-administered with R/F/TAF modestly increased plasma TFV exposure, however, TFV area under the curve (AUC) levels remained substantially lower than TFV exposures from TDF-containing regimens (362 vs 2000-5000 ng.h/mL; R/F/TAF + LDV/SOF vs R/F/ approved compounds or indication the IPD will be available for request 6 months after FDA and EMA approval.…”

Contemporary Drug–Drug Interactions in HIV Treatment

“…Therefore, while an interaction is possible, there has been no short‐term evidence of clinical consequences. While exposure increases 1.4‐fold when coadministered with boosted DRV, this is not considered clinically significant …”

Darunavir–cobicistat–emtricitabine–tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era

“… 14 A study on the effect of food on Taf pharmacokinetics showed that Taf exposure decreased in fasting conditions. 15 However, no significant trend in exposure response/safety regarding Taf exposure was found in fasting or fed conditions. 11 …”

“…It also lacks the induction activity of Rtv on several enzymes and transporters, including CYP isoenzymes, Pgp, and glucuronyltransferases. 15 , 31 , 32 …”