Asunaprevir: A Review of Preclinical and Clinical Pharmacokinetics and Drug–Drug Interactions

Abstract

Asunaprevir is a tripeptidic acylsulfonamide inhibitor of the hepatitis C virus (HCV) NS3/4A protease. Asunaprevir undergoes rapid absorption, with a time to reach maximum plasma concentration (T max) of 2-4 h and an elimination half-life (t ½) of ≈15-20 h observed in single-ascending dose studies. Steady state was achieved by day 7 in multiple-ascending dose studies. The large food effect observed with earlier formulations was mitigated by the soft-gel capsule. Asunaprevir demonstrates high apparent oral clearance and minimal renal elimination, and is eliminated primarily via cytochrome P450 (CYP) 3A4-mediated hepatic oxidative metabolism and faecal excretion. Highly preferential distribution of asunaprevir to the liver occurs via organic anion-transporting polypeptide (OATP)-mediated transport and results in low plasma concentrations. The condition of the liver affects disposition, as higher asunaprevir plasma exposures are observed in patients infected with HCV and/or hepatic impairment. Japanese patients also have higher exposure relative to North American/European patients, but comparable safety at the registrational dose. Asunaprevir has a low potential to perpetrate drug-drug interactions via CYP3A4, P-glycoprotein and OATP, but is a moderate CYP2D6 inhibitor; concomitant drugs that are substrates of CYP2D6 or P-glycoprotein and have a narrow therapeutic index should be used with care. Asunaprevir plasma exposure is strongly affected by inhibitors of OATP transport. No clinically significant interactions were observed between asunaprevir and daclatasvir or daclatasvir/beclabuvir. Asunaprevir has a complex pharmacokinetic profile and forms part of potent and well-tolerated all-oral regimens for the treatment of chronic HCV infection.

Population Pharmacokinetic Analysis for Daclatasvir and Asunaprevir in Japanese Subjects With Chronic Hepatitis C Virus Infection

“…The result was similar to the findings in AI447017 (the phase 2 study used a 200‐mg tablet formulation) and AI447026 (the phase 3 study used the 100‐mg soft‐gel capsule). The observed asunaprevir AUC in AI447017 and AI447026 was 2950 and 2155 ng·h/mL, respectively . In addition, the trend was consistent with the result of the relative bioavailability study.…”

“…Consequently, the 4 categories of OATP1B1 haplotypes did not show statistical significance, suggesting that in the Japanese population, genetic variability of OATP1B1 has no impact on asunaprevir exposure. Other investigations had been evaluated by including non‐Japanese data, and the analyses did not reveal a relationship between OATP and asunaprevir exposure …”

Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study

“…The pharmacokinetic examination of the blood level of the drugs in patient on dialysis has previously been reported in other countries. The AUC of DCV has been reported to be 26.9% higher in patients on dialysis than in control patients with normal renal function, and the AUC of ASV has been reported to be 10.1% lower in dialysis patients than in patients with normal renal function . However, the examination of Japanese patients on dialysis has not been performed, and the pharmacokinetic examination of both drugs in combination has not been conducted sufficiently in other countries.…”

“…We performed the blood level of the drug on the day of dialysis for two reasons. The first is that DCV and ASV have a high protein‐binding rate together and a large molecular weight . Thus, the pharmacokinetics are not different on the day of dialysis because the drugs were less likely to be removed by dialysis.…”

A Review of Daclatasvir Drug–Drug Interactions

“…There are no clinically significant DDIs between DCV and ASV (Studies AI447-009 and AI447-011) [16, 17], ASV and BCV in combination (Study AI443-014) [18], or SOF (Study AI444-040) [19], and dose modifications during co-administration are not required. No dose adjustments are required during the co-administration of DCV with simeprevir (Study HCP1005) [20].…”