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

Abstract

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.Electronic supplementary materialThe online version of this article (10.1007/s40268-017-0222-8) contains supplementary material, which is available to authorized users.

Beclabuvir can Inhibit the RNA-dependent RNA Polymerase of Newly Emerged Novel Coronavirus (SARS-CoV-2)

“…Nowadays, different antiviral strategies such as, capping the virus particle which enables tethering within 549-776 amino acid residues (GO:0003968) and this stretch of amino acids is crucial for RNA synthesis (Figure 3). Beclabuvir is a non-nucleoside polymerase inhibitor that potentially inhibit nonstructural protein 5B (NS5B) of HCV (Garimella, Tao et al 2018). Upon intracellular uptake beclabuvir allosterically binds to the noncatalytic Thumb 1 site (Figure 4) of viral RdRp which slowdown the RNA synthesis process (Garimella, Tao et al 2018).…”

“…Beclabuvir is a non-nucleoside polymerase inhibitor that potentially inhibit nonstructural protein 5B (NS5B) of HCV (Garimella, Tao et al 2018). Upon intracellular uptake beclabuvir allosterically binds to the noncatalytic Thumb 1 site (Figure 4) of viral RdRp which slowdown the RNA synthesis process (Garimella, Tao et al 2018). However, in the case of SARS-CoV-2 beclabuvir occupies the active site environment (ASE), ( Figure 5) of the RdRp which is essential for the RNA-dependent polymerase activity (Fouad, Soliman et al 2019) ).…”

Beclabuvir can Inhibit the RNA-dependent RNA Polymerase of Newly Emerged Novel Coronavirus (SARS-CoV-2)

“…Results of the present study suggest that ATP binding domain and RNA-directed 5'-3' polymerase activity of the RdRp exist within 549 th to 776 th amino acid residues (GO:0003968) and this stretch of amino acids is crucial for RNA synthesis (Figure 3). Beclabuvir is a non-nucleoside polymerase inhibitor that potentially inhibit nonstructural protein 5B (NS5B) of HCV [25]. Previous studies, including phase 3 clinical trials have suggested beclabuvir have a high response rate at post-treatment week [26,27].…”

“…Moreover, the pharmacokinetic, efficiency and tolerability were also reported very favorable [28]. Upon intracellular uptake beclabuvir allosterically binds to the non-catalytic Thumb 1 site (Figure 4) of viral RdRp which slowdown the RNA synthesis process [25]. However, in the case of RdRpSARS-CoV-2 beclabuvir occupies the active site environment (ASE), ( Figure 5) is essential for the RNA-dependent polymerase activity [18,19] ).…”

Cardiovascular Risk Management and Hepatitis C: Combining Drugs

“…The drug interaction between metoprolol and daclatasvir/asunaprevir/beclabuvir has been studied in vivo [ 20 ] (Table 3 ); however, this regimen is not licensed in Europe and the USA. Garimella and colleagues [ 20 ] showed that asunaprevir affected the metoprolol plasma concentration as it is a moderate inhibitor of CYP2D6. In vitro experiments have shown that daclatasvir is not an inhibitor of CYP2D6 [ 20 – 22 ].…”