Pharmacokinetics and Pharmacodynamics of Pegylated Interferon Lambda-1 in Cynomolgus Monkeys

Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFN lambda) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 phosphorylation) and expression of interferon-stimulated genes (ISGs) by pegIFN lambda were assessed in, respectively, cynomolgus monkey leukocyte subsets and hepatocytes stimulated in vitro. ISG induction by pegIFN lambda or IFN alpha was also assessed in peripheral leukocytes and liver biopsies after single and repeat (x3) dosing of pegIFN lambda (0.03, 0.3, 3.0 mg/kg) or unpegylated IFN alpha-2b (10(7) IU/kg). Single-dose pharmacokinetics of pegIFN lambda were evaluated. Strong ISG induction occurred in cultured hepatocytes and liver biopsies with both pegIFN lambda and IFN alpha. However, STAT1 phosphorylation, MHC class 1 upregulation, and ISG induction in leukocytes only occurred with IFN alpha. Serum neopterin was unaffected by pegIFN lambda; however, beta-2-microglobulin was elevated at all doses. The terminal half-life of pegIFN lambda 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 pegIFN lambda. Additionally, the absence of pegIFN lambda pharmacologic activity in leukocytes is consistent with its low receptor expression in blood.