title: PEGylated interferon displays differences in plasma clearance and bioavailability between male and female mice and between female immunocompetent C57Bl/6J and athymic nude mice.
abstract: Gender and immune status can considerably impact on the pharmacokinetics (PK) of macromolecular and small molecule drugs. However, these effects are often not considered in drug development. We aimed to quantitatively evaluate effects of gender and immune status on the PK of PEGylated interferon in frequently used murine models. Chronically cannulated female athymic nude and female and male immunocompetent C57Bl/6J mice (n = 24 in total) received a single intravenous or subcutaneous (s.c.) dose of PEGylated interferon. Serial blood samples were taken for 48 h. Noncompartmental analysis and population PK modeling with covariate analysis were performed to evaluate the data. The PK of PEGylated interferon followed a three compartment disposition model with two sequential compartments for s.c. absorption. Female nude mice had significantly higher plasma clearance than C57Bl/6J mice (0.503 vs. 0.397 mL/h). Male mice had a slower absorption rate constant (0.138 h(-1)) and extent (46.2%) of s.c. absorption than female mice (0.274 in C57Bl/6J and 0.374 h(-1) in nude, 60.8% in both). Thus, gender and immune status significantly impacted on important PK parameters of PEGylated interferon in murine models commonly utilized in drug development. It is critical to take into account these differences when choosing animal models and conducting translational pharmacology research.
authors.affiliation: Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, 3052, Australia.
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Caliph
authors.forename: David M
authors.initials: DM
authors.lastname: Shackleford
authors.forename: David B
authors.initials: DB
authors.lastname: Ascher
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kaminskas
mesh_terms: D000818:Animals; D001682:Biological Availability; D005260:Female; D007121:Immunocompetence / Q000187:drug effects / Q000502:physiology*; D007372:Interferons / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D012727:Sex Characteristics
chemical_list: D011092:Polyethylene Glycols; D007372:Interferons
keywords: absorption; bioavailability; elimination; gender; macromolecular drug delivery; mathematical model; pegylation; pharmacokinetics; population pharmacokinetics