Derivation of Phase 3 dosing for peginterferon lambda-1a in chronic hepatitis C, Part 1: Modeling optimal treatment duration and sustained virologic response rates

J Clin Pharmacol. 2015 Jan;55(1):63-72. doi: 10.1002/jcph.363. Epub 2014 Jul 24.

Abstract

Peginterferon lambda-1a (Lambda) is under clinical development for the treatment of chronic hepatitis B and C virus (HBV, HCV, respectively) infection. This is the first of two manuscripts detailing the pharmacodynamic derivation of Lambda dosing and treatment durations for Phase 3 studies in HCV, based on Phase 2 data. We describe here the derivation of a population model of Lambda exposure; the adaptation of a previously published viral dynamic model for Lambda treatment and host genotype, and its use to simulate sustained virologic responses (SVR). Lambda population pharmacokinetics was described by a one-compartment model with first-order absorption, and 33.0 L per day clearance with 47% interindividual (36% intra-individual) variability. Weight explained a negligible proportion of the variability. Based on SVR predictions, optimum treatment durations were 48 weeks for HCV genotypes 1 or 4 (SVR estimates for 120, 180, and 240 μg Lambda: 58%, 54%, 47%, respectively) and 24 weeks for genotypes 2 or 3 (75%, 72%, 67%). SVR predictions for 240 μg were lower due to dropout predictions. The SVR model established the optimum treatment duration for Phase 3 studies but did not differentiate between 120 and 180 μg dosing. A companion manuscript describes dose selection based on exposure-response/safety modeling.

Trial registration: ClinicalTrials.gov NCT01001754.

Keywords: dose-selection; exposure-response models; pharmacodynamics; simulation.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / pharmacokinetics
  • Antiviral Agents* / therapeutic use
  • Clinical Trials, Phase III as Topic
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Genotype
  • Hepacivirus / drug effects
  • Hepacivirus / genetics
  • Hepacivirus / physiology
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / genetics
  • Hepatitis C, Chronic / metabolism
  • Hepatitis C, Chronic / virology
  • Humans
  • Interferon-alpha / therapeutic use
  • Interferons
  • Interleukins* / administration & dosage
  • Interleukins* / genetics
  • Interleukins* / pharmacokinetics
  • Interleukins* / therapeutic use
  • Male
  • Middle Aged
  • Models, Biological*
  • Polyethylene Glycols* / administration & dosage
  • Polyethylene Glycols* / pharmacokinetics
  • Polyethylene Glycols* / therapeutic use
  • RNA, Viral / analysis
  • Recombinant Proteins / therapeutic use
  • Ribavirin / therapeutic use
  • Viral Load / drug effects

Substances

  • Antiviral Agents
  • interferon-lambda, human
  • Interferon-alpha
  • Interleukins
  • RNA, Viral
  • Recombinant Proteins
  • peginterferon lambda-1a
  • Polyethylene Glycols
  • Ribavirin
  • Interferons
  • peginterferon alfa-2a

Associated data

  • ClinicalTrials.gov/NCT01001754