Exposure‐Response (Efficacy) Analysis of Daclatasvir and Asunaprevir in Japanese Patients With Hepatitis C Virus Infection

Abstract

The treatment of hepatitis C virus (HCV) infection has been revolutionized by the development of all‐oral combination regimens of direct‐acting antiviral agents. The current analysis characterized the relationship between exposures of daclatasvir (DCV; tablets) and asunaprevir (ASV; capsules) and sustained virologic response (SVR) in Japanese patients who are HCV genotype (GT) 1b nonresponders to pegylated interferon (IFN) α/ribavirin or IFNβ/ribavirin, and IFN‐based therapy–ineligible naive/intolerant patients receiving DCV and ASV, and provided insight into patient covariates that were most closely associated with efficacy. The relationship between the probability of achieving SVR at 12 weeks after treatment (SVR12) and average steady‐state plasma concentrations estimated from population pharmacokinetic models for DCV and ASV is described using a logistic regression model with data from a phase 2 and a phase 3 study in Japanese patients infected with HCV GT 1b (N=265). The functional form characterization, which describes a relationship between DCV and ASV average steady‐state plasma concentrations and SVR12, as well as covariate identification (demographic, laboratory, and prognostic and treatment covariates) were investigated during model development. The presence of the signature nonstructural protein 5A Y93H mutation at baseline was the only significant parameter of SVR12 in the final exposure‐response model. Model evaluation plots demonstrate that the final model was able to predict the observed SVR rates. Exposure‐response analysis supports the clinical utility of the combination regimen of 60‐mg once‐daily DCV and 100‐mg twice‐daily ASV in Japanese patients infected with HCV GT 1b.

Exposure‐Response Analysis for Efficacy of Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV‐Infected Patients

“…A previous analysis exploring the E-R of SVR12 with the daclatasvir and asunaprevir regimen in Japanese subjects with HCV GT 1b infection who were ineligible-naive/intolerant to IFN-based therapy or prior nonresponders revealed a shallow but significant relationship with daclatasvir exposure only. 24 In the current analysis neither E-R relationship was well estimated in the final model; however, of the 3 E-R relationships, the daclatasvir relationship was the best characterized with a 55.5% relative standard error, substantially lower than the percentage relative standard error for asunaprevir and beclabuvir (155% and 585%, respectively). That analysis data set was restricted to GT 1b patients, but the most numerous genotype in the current analysis was GT 1a.…”

“…The magnitude of the effect was not considered clinically meaningful. A previous analysis exploring the E‐R of SVR12 with the daclatasvir and asunaprevir regimen in Japanese subjects with HCV GT 1b infection who were ineligible‐naive/intolerant to IFN‐based therapy or prior nonresponders revealed a shallow but significant relationship with daclatasvir exposure only …”