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

J Clin Pharmacol. 2018 Nov;58(11):1468-1478. doi: 10.1002/jcph.1274. Epub 2018 Jul 31.

Abstract

Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all-oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed-effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively. The plasma pharmacokinetic profiles of daclatasvir and asunaprevir were described by a 1-compartment model. Parameter estimates (interindividual variability) of daclatasvir apparent clearance (CL/F) and apparent volume of the central compartment (V/F) were 5.29 L/h (39.4%) and 64.2 L (38.1%). The effects of all statistically significant covariates on daclatasvir PK parameters were within or overlapped the 80% to 125% boundaries, suggesting a lack of clinical relevance. Parameter estimates (interindividual variability) of asunaprevir CL/F and V/F were 52.1 L/h (41.5%) and 75.1 L (93.4%), respectively. Baseline and time-varying aspartate aminotransferase (AST) and cirrhosis on CL/F and formulation (soft-gel capsule or tablet) on F were included as significant covariates in the asunaprevir popPK model. The effects of all covariates exceeded the 80% to 125% boundaries, indicating that the asunaprevir soft-gel capsule had higher bioavailability than the tablet and that asunaprevir exposure increased with cirrhosis and increasing baseline and time-varying AST values. The popPK models adequately described the PK profiles of daclatasvir and asunaprevir in Japanese HCV subjects.

Keywords: Japanese; asunaprevir; clinical pharmacology; daclatasvir; hepatitis C virus; pharmacometrics; population pharmacokinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / therapeutic use
  • Carbamates
  • Drug Therapy, Combination
  • Female
  • Hepatitis C, Chronic / drug therapy*
  • Humans
  • Imidazoles / pharmacokinetics*
  • Imidazoles / therapeutic use
  • Isoquinolines / pharmacokinetics*
  • Isoquinolines / therapeutic use
  • Japan
  • Liver Cirrhosis / drug therapy
  • Male
  • Middle Aged
  • Models, Biological
  • Pyrrolidines
  • Sulfonamides / pharmacokinetics*
  • Sulfonamides / therapeutic use
  • Valine / analogs & derivatives

Substances

  • Antiviral Agents
  • Carbamates
  • Imidazoles
  • Isoquinolines
  • Pyrrolidines
  • Sulfonamides
  • Valine
  • daclatasvir
  • asunaprevir