Population Pharmacokinetics and Pharmacodynamics of Albinterferon Alfa-2b in Patients Treated for Hepatitis C Virus Genotype 2/3

Jing      Yu; Haiying      Sun; Maria      Pang; Wan-Long      Chuang; Shiv K.      Sarin; Robert      Flisiak; Daniel S.      Stein

Abstract

Albinterferon alfa-2b (albIFN) has been studied for the treatment of chronic hepatitis C virus infection in combination with ribavirin at different dose regimens ranging 900-1500 g once every 2 (q2w) or 4 (q4w) weeks. Analyses on efficacy and safety exposure-response relationships in Genotype2/3 (G2/3) interferon-naïve patients were conducted to explore an improved risk-benefit of therapy. Data from 972 G2/3 patients were included in the exposure-response analysis. Major antiviral response endpoints of Sustained Virologic Response (SVR) and Rapid Virologic Response (RVR) exposure- response were modeled using logistic regression. The reported adverse event AE frequencies were tabulated vs quartiles of albIFN exposure. Body weight based exposure were estimated based on the population pharmacokinetic (PK) model and simulations were performed according to the weight based exposure and the exposure-response relationship. Within the G2/3 interferon-naive patients, albIFN Cavg but not Cmax or Cmin was associated with efficacy, along with certain baseline characteristics. For a given Cavg, dosing q2w was more active than q4w for RVR; Cavg was modestly associated with SVR, while no effect of dose interval was observed. Cavg was associated with a number of adverse events and laboratory abnormalities, especially at the higher exposure quartiles. The weight-based dose regimen (20 µg/kg) was predicted to decrease the subjects in the higher two quartiles of exposure by about half, compared with the fixed 1500 g dose. This potential improvement was predicted to have a better overall safety profile with similar efficacy, but the overall reduction in AE’s would be small. As albIFN Cavg was significantly associated with both efficacy and safety outcomes, a weight-based regimen would be unlikely to significantly improve the risk benefit in comparison to the standard of care.

Keywords: Albinterferon alfa-2b, chronic hepatitis C virus, exposure-response, rapid virologic response, sustained virologic response, safety.