Min Zhu, Vijay Batra and Farkad Ezzet
Schering-Plough Research Institute, Kenilworth, NJ, USA
Objective To establish a pharmacokinetic-pharmacodynamic model for interferon alpha-2b (Intron A) and its clinical endpoints in hepatitis-C patients.
Methods Despite the clinical efficacy of Intron A in the treatment of hepatitis-C, a direct correlation between drug serum concentration and clinical endpoints, e.g. alanine aminotransferase (ALT) and hepatitis-C virus (HCV), could not be established. Recent publications have indicated that MX protein, stimulated by Intron A, has an inhibitory effect on ALT and HCV levels. We evaluated these findings using data obtained from 10 hepatitis-C patients who received multiple subcutaneous doses (3 times/week) of Intron A (3 MIU) for 4 weeks. Serum drug concentrations were determined over 24 h following the last dose using a validated immunoassay. Serum ALT (and HCV) were measured at pre-dose and once weekly for 10 weeks, thereafter. Concentrations of MX protein were not measured in this study, but were calculated using a previously published Indirect Response (IR) model with Intron A as the inducer. MX was then correlated with either ALT or HCV in a second IR model. The inhibitory effects of MX were determined by the inhibition rate constants (Kin) and the MX concentration producing 50% of maximum inhibition (IC50). The pharmacokinetics of Intron A together with MX stimulation and ALT (or HCV) inhibition were modeled simultaneously using NONMEM V.
Results Population elimination rate constant (Ke) and volume of distribution (V/F) of Intron A were 0.20 1/h and 37 L, respectively. The corresponding inter-subject variability was 40% and 29%. Higher Intron A levels resulted in higher production of MX, which in turn resulted in lower ALT or HCV levels (p<0.01). Kin and IC50 were estimated to be 2.4E-6 titer/h and 1.55 ug/ml for HCV and 0.20 IU/h and 0.62 ug/ml for ALT. Pronounced inter-subject variability (>100%) was found for both Kin and IC50.
Conclusions Intron A displayed a significant lag time between drug administration and the clinical responses. The utilization of MX protein as a link helped to determine Intron A inhibitory effects on hepatitis-C.
Reference: PAGE 10 (2001) Abstr 184 [www.page-meeting.org/?abstract=184]
Poster: poster