Dose Modification Not Needed in Coadministration of an HIV, HCV Tx

Dose Modification Not Needed in Coadministration of an HIV, HCV Tx
Dose Modification Not Needed in Coadministration of an HIV, HCV Tx

SAN DIEGO, CA—Coadministration of tenofovir alafenamide-based single tablet regimens for HIV with ledipasvir/sofosbuvir does not require dose modification, results from a drug-drug interaction study presented at IDWeek 2015 has shown.

About one-third of HIV patients have a co-infection with hepatitis C virus (HCV).  Concomitant use of antivirals to treat HCV (eg, ledipasvir) with antiretrovirals for HIV (eg, tenofovir alafenamide) may conflict with drug-drug interactions, as ledipasvir is a P-glycoprotein (P-gp) inhibitor and tenofovir alafenamide is a P-gp substrate.

Joseph Custodio, PhD, and colleagues from Gilead Sciences, Inc., Foster City, CA, conducted studies to evaluate drug-drug interactions between tenofovir alafenamide-based regimens rilpivirine/emtricitabine/tenofovir alafenamide (R/F/TAF) or elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) and the fixed-dose combination of ledipasvir/sofosbuvir (LDV/SOF),  an anti-HCV agent.

Study 1 (n=42) and Study 2 (n=30) were multi-dose, randomized, crossover studies evaluated healthy volunteers that received R/F/TAF 25mg/200mg/24mg (Study 1) or E/C/F/TAF 150mg/150mg/200mg/10mg (Study 2), alone or in combination with LDV/SOF daily with food for 11 (Study 1) or 10 (Study 2) days.

Dr. Custodio and team analyzed plasma concentrations of rilpivirine, elvitegravir, cobicistat, emtricitabine, tenofovir alafenamide and its metabolite (TFV), ledipasvir, sofosbuvir and its metabolite (GS-331007). Pharmacokinetic parameters were calculated via non-compartmental analysis. Geometric least squares mean ratio (combination vs. alone) and 90% confidence intervals for the analytes' AUC, Cmax, Ctau were figured by linear mixed effect modeling and compared to lack of alteration bounds.

Across both studies, treatments were generally well tolerated. The GLSM and 90% confidence intervals for all analytes were contained within the prespecified bounds except TFV when RPV/FTC/TAF was coadministered with LDV/SOF. Another exception was observed with cobicistat when E/C/F/TAF was coadministered with LDV/SOF; and with LDV/SOF when coadministered with E/C/TAF.

Though the TFV exposure was increased following coadministration of R/F/TAF + LDV/SOF, the mean TFV AUCtau was approximately 5 times lower than TFV vs. TDF. It remained within the range of TFV where it did not lead to renal adverse events or bone loss (E/C/F/TAF). “There was no association between higher cobicistat exposure and incidence of adverse events and renal function parameters,” added Dr. Custodio. The higher exposures of LDV and SOF were still in the exposure-safety range, supporting the conclusion that R/F/TAF or E/C/TAF may be coadministered with LDV/SOF without altering the dose.  

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