Effects of a Fixed-Dose Co-Formulation of Daclatasvir, Asunaprevir, and Beclabuvir on the Pharmacokinetics of a Cocktail of Cytochrome P450 and Drug Transporter Substrates in Healthy Subjects

摘要

BackgroundA fixed-dose combination of daclatasvir (DCV; hepatitis C virus NS5A inhibitor), asunaprevir (ASV; non-structural protein 3 inhibitor), and beclabuvir (BCV; non-structural protein 5B inhibitor) is approved in Japan for hepatitis C virus genotype 1. ObjectiveThe objective of this study was to assess the combination’s drug–drug interaction potential in vivo using a validated cocktail of eight cytochrome P450 (CYP) and transporter probes. MethodsWe conducted an open-label single-sequence study in healthy adults ( n = 20) given single-dose caffeine (CYP1A2 substrate), metoprolol (CYP2D6), flurbiprofen (CYP2C9), montelukast (CYP2C8), omeprazole (CYP2C19), midazolam (CYP3A4), digoxin (P-glycoprotein), and pravastatin (organic anion-transporting polypeptide), alone or with steady-state twice-daily DCV/ASV/BCV 30/200/75?mg (with or without additional BCV 75?mg to adjust for higher exposure in hepatitis C virus infection). ResultsDaclatasvir/asunaprevir/beclabuvir did not affect CYP1A2, CYP2C8, or CYP2C9; the probe maximum observed concentration and area under the concentration–time curve extrapolated to infinite time geometric mean ratios and 90% confidence intervals were all within the 0.8–1.25 bioequivalence range. Beclabuvir showed moderate dose-dependent CYP2C19 induction; omeprazole maximum observed concentration and area under the concentration–time curve from 0 to the last quantifiable concentration were lower with additional BCV [geometric mean ratio 0.36 (90% confidence interval 0.23–0.55) and 0.34 (0.25–0.46), respectively] than without [0.57 (0.42–0.78), 0.48 (0.39–0.59)]. Weak-to-moderate CYP3A4 induction was observed, plus weak CYP2D6, P-glycoprotein, and organic anion-transporting polypeptide inhibition [maximum observed concentration and area under the concentration–time curve extrapolated to infinite time without additional BCV: midazolam 0.57 (0.50–0.65), 0.53 (0.47–0.60); metoprolol 1.40 (1.20–1.64), 1.71 (1.49–1.97); digoxin 1.23 (1.12–1.35), 1.23 (1.17–1.29); pravastatin 2.01 (1.63–2.47), 1.68 (1.43–1.97)]. ConclusionsNo dose adjustments with DCV/ASV/BCV are indicated for CYP1A2, CYP2C8, CYP2C9, or P-glycoprotein substrates. CYP3A4, CYP2D6, and OATP substrates should be co-administered with caution. Co-administration with agents solely metabolized by CYP2C19 is not recommended.