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

• Published in: Journal of clinical pharmacology Vol. 55; no. 1; p. 63
• Main Authors: Wang, Xiaodong, Hruska, Matthew, Chan, Phyllis, Ahmad, Alaa, Freeman, Jeremy, Horga, Maria Arantxa, Hillson, Jan, Kansra, Vikram, Lopez-Talavera, Juan-Carlos
• Format: Journal Article
• Language: English
• Published: England 01.01.2015
• Subjects: 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; Recombinant Proteins - therapeutic use; Ribavirin - therapeutic use; RNA, Viral - analysis; Viral Load - drug effects; pharmacodynamics; simulation; dose-selection; exposure-response models
• ISSN: 1552-4604
• DOI: 10.1002/jcph.363

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.