title: Pharmacokinetics and pharmacodynamics of pegylated interferon lambda-1 in cynomolgus monkeys.
abstract: Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFNλ) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 phosphorylation) and expression of interferon-stimulated genes (ISGs) by pegIFNλ were assessed in, respectively, cynomolgus monkey leukocyte subsets and hepatocytes stimulated in vitro. ISG induction by pegIFNλ or IFNα was also assessed in peripheral leukocytes and liver biopsies after single and repeat (x3) dosing of pegIFNλ (0.03, 0.3, 3.0 mg/kg) or unpegylated IFNα-2b (10(7) IU/kg). Single-dose pharmacokinetics of pegIFNλ were evaluated. Strong ISG induction occurred in cultured hepatocytes and liver biopsies with both pegIFNλ and IFNα. However, STAT1 phosphorylation, MHC class 1 upregulation, and ISG induction in leukocytes only occurred with IFNα. Serum neopterin was unaffected by pegIFNλ; however, β-2-microglobulin was elevated at all doses. The terminal half-life of pegIFNλ was 23 h with a 59 mL/kg volume of distribution, consistent with other pegylated IFNs. Serum exposure was dose-proportional across the dosing range. These data demonstrate the suitability of cynomolgus monkeys for the preclinical evaluation of pegIFNλ. Additionally, the absence of pegIFNλ pharmacologic activity in leukocytes is consistent with its low receptor expression in blood.
authors.affiliation: Department of Preclinical Development, ZymoGenetics, Inc., Seattle, WA 98102, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Byrnes-Blake
authors.forename: Susan
authors.initials: S
authors.lastname: Pederson
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Klucher
authors.forename: Monica
authors.initials: M
authors.lastname: Anderson-Haley
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Miller
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Lopez-Talavera
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Freeman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D007372:Interferons; D007378:Interleukins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008252:Macaca fascicularis; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000737:chemistry; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000095022:Interferon Lambda
chemical_list: D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D050794:STAT1 Transcription Factor; C000624353:interferon-lambda, human; D000095022:Interferon Lambda