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

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.

• Authors: Mayu Osawa, Takayo Ueno, Hiroki Ishikawa, Yasuhiko Imai, Tushar Garimella
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 58 Issue 11 Pg. 1468-1478 (11 2018) ISSN: 1552-4604 [Electronic] England
• PMID: 30063254 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Chemical References

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

Topics

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