Pharmacokinetics, Safety, and Tolerability of Ravidasvir, with and without Danoprevir/Ritonavir, in Healthy Subjects

Abstract

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug-drug interactions between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In the 1st study, healthy volunteers were administered single oral doses of 100, 200, and 300 mg of RDV and 200 mg once daily for 7 days. The 2nd study was a randomized, double-blinded, and placebo-controlled sequential design (day 1 for 200 mg of RDV alone, day 7 for 100 mg/100 mg of DNVr, day 13 for 200 mg of RDV plus 100 mg/100 mg DNVr, followed by 200 mg of RDV once daily with 100 mg/100 mg of DNVr twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Coadministration with DNVr (100 mg/100 mg, twice daily) resulted in a 2.92-fold and 1.99-fold increase in minimum plasma concentration at steady state (Cmin,ss) and area under the concentration-time curve at steady state (AUCτ) of RDV, respectively. With coadministration of RDV, maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 12 h (AUC0-12) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir's continued clinical development and treatment. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT03430830 and NCT03288636.).

Keywords: drug-drug interactions; hepatitis C; pharmacokinetics; ravidasvir; safety.

Figures

FIG 1

Study design. Note: all drugs were taken under nonfasting conditions by the participants. Treatment A, single-dose administration of 100 mg of RDV; treatment B, single-dose administration of 200 mg of RDV; treatment C, single-dose administration of 300 mg of RDV. SEQ, sequence; RDV, ravidasvir; DNVr, ritonavir-boosted danoprevir.

FIG 2

Concentration-time profiles (means plus standard deviations) for ravidasvir, danoprevir, and ritonavir. Note: period 1, day 1, subjects received a single dose of 200 mg of RDV; period 2, day 7, subjects received a single dose of DNVr (100 mg/100 mg); period 3, day 13, subjects received a single dose of 200 mg RDV + DNVr (100 mg/100 mg); and period 3, day 23, included the final days of administration of antiretroviral therapy (RDV 200 mg once daily + DNVr twice daily). RDV, ravidasvir; DNVr, ritonavir-boosted danoprevir; QD, once a day.

FIG 3

Pharmacokinetic effects of ravidasvir coadministered with danoprevir/ritonavir. (A) Single-dose study phase adjusted GMR (90% CI) of coadministered drug AUC and Cmax (adjusted for effects in the analysis of variance model). (B) Multiple-dose study phase adjusted GMR (90% CI) of ravidasvir AUCτ, Cmax,ss, and Cmin,ss with/without administration of DNVr. AUC0–12, area under the plasma concentration-time curve from time 0 to 12 h; AUC0–24, area under the plasma concentration-time curve from time 0 to 24 h; AUCτ, area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval τ; CI, confidence interval; Cmax, maximum plasma concentration; Cmin,ss, the minimum plasma concentration at steady state; ss, steady state.