A once-daily fixed-dose combination tablet composed of sofosbuvir (SOF; nucleotide analog NS5B inhibitor) and velpatasvir (VEL, GS-5816; pangenotypic NS5A inhibitor) is in clinical development for the treatment of chronic HCV infection. Phase 1 studies were conducted in healthy volunteers to evaluate potential drug-drug interactions (DDIs) between SOF/VEL and HIV antiretroviral (ARV) regimens containing a pharmacokinetic “booster” (RTV or COBI) to support their use together in HIV/HCV co-infected patients.
These were multiple-dose, randomized, cross-over DDI studies. Subjects received SOF/VEL and ARV regimens (EVG/COBI/FTC/TDF, FTC/TDF+DRV/r, FTC/TDF+ATV/r, FTC/TDF+LPV/r, and EVG/COBI/FTC/TAF) alone and in combination. Steady-state plasma concentrations of SOF, its predominant circulating nucleoside metabolite GS-331007, VEL, and ARVs were analyzed on the last day of dosing for each treatment and PK parameters were calculated. Geometric least-squares means ratios and 90% confidence intervals (combination vs. alone) for SOF, GS-331007, VEL, and ARV AUCtau, Cmax and Ctau were estimated and compared against lack of PK alteration boundaries of 70-143% for all analytes. Safety assessments were conducted throughout the study.
123 of 129 enrolled subjects completed the studies; 5 subjects withdrew consent and 1 discontinued due to pregnancy. The majority of adverse events (AEs) were Grade 1 and there were no discontinuations due to AEs and no serious AEs. SOF AUC increased 37% with EVG/COBI/FTC/TAF, decreased ~30% with FTC/TDF+DRV/r or LPV/r, and was unchanged with other regimens. GS-331007 AUC increased 48% with EVG/COBI/FTC/TAF and was unchanged with other regimens. VEL AUC increased 58% with EVG/COBI/FTC/TAF, increased 142% with FTC/TDF+ATV/r, and was unchanged with other regimens. No clinically significant changes in the PK of EVG, COBI, DRV, ATV, LPV, RTV, FTC, and TAF were observed when administered with SOF/VEL. Increased TFV exposure (~40%) was observed with SOF/VEL when administered as TDF. No increase in TFV exposure was observed when administered as TAF.
Study treatments were generally well tolerated. Results from this study demonstrate that SOF/VEL may be administered with EVG, COBI, DRV/r, ATV/r, and LPV/r with a backbone of FTC/TDF or FTC/TAF. The safety and efficacy of SOF/VEL and ARVs will be evaluated in clinical studies of HIV/HCV coinfected subjects.