title: Derivation of Phase 3 dosing for peginterferon lambda-1a in chronic hepatitis C, Part 1: Modeling optimal treatment duration and sustained virologic response rates.
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.
authors.affiliation: Genentech, South San Francisco, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Matthew
authors.initials: M
authors.lastname: Hruska
authors.forename: Phyllis
authors.initials: P
authors.lastname: Chan
authors.forename: Alaa
authors.initials: A
authors.lastname: Ahmad
authors.forename: Jeremy
authors.initials: J
authors.lastname: Freeman
authors.forename: Maria Arantxa
authors.initials: MA
authors.lastname: Horga
authors.forename: Jan
authors.initials: J
authors.lastname: Hillson
authors.forename: Vikram
authors.initials: V
authors.lastname: Kansra
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Lopez-Talavera
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D017326:Clinical Trials, Phase III as Topic; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D012367:RNA, Viral / Q000032:analysis; D011994:Recombinant Proteins / Q000627:therapeutic use; D012254:Ribavirin / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C000600496:peginterferon lambda-1a; C100416:peginterferon alfa-2a
keywords: dose-selection; exposure-response models; pharmacodynamics; simulation