title: In vivo pharmacology and toxicology evaluation of polyethylene glycol-conjugated interferon beta-1a.
abstract: Human interferon (IFN) β has well established beneficial effects in treating relapsing forms of multiple sclerosis, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20-kDa polyethylene glycol (PEG)-conjugated IFN β-1a (PEG-IFN β-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. We present pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN β-1a in Rhesus monkeys in support of a phase 1 clinical trial. Two single-dose PK/PD studies and one 5-week repeat-dose toxicity study compliant with good laboratory practice were conducted. The PK of IFN β-1a and PEG-IFN β-1a were modeled with a two-compartment model, and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN β-1a showed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN β-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN β-1a resulted in the elevation of neopterin concentration, a transient body temperature increase, and a reversible lymphocyte count decrease. As expected, neutralizing antibodies to PEG-IFN β-1a formed in almost all monkeys after 5 weeks of treatment, which resulted in significantly reduced drug exposure and abrogation of neopterin induction. There were no drug-related adverse effects at doses up to 100 μg/kg (11 MIU/kg) given subcutaneously or intramuscularly once weekly for 5 weeks. The no-observed-adverse-effect level was determined to be 100 μg/kg (11 MIU/kg), the highest dose tested.
authors.affiliation: Biogen Idec Inc, Cambridge, Massachusetts 02142, USA. xiao.hu@biogenidec.com
authors.forename: Xiao
authors.initials: X
authors.lastname: Hu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Olivier
authors.forename: Evelyne
authors.initials: E
authors.lastname: Polack
authors.forename: Mary
authors.initials: M
authors.lastname: Crossman
authors.forename: Katie
authors.initials: K
authors.lastname: Zokowski
authors.forename: Robert S
authors.initials: RS
authors.lastname: Gronke
authors.forename: Suezanne
authors.initials: S
authors.lastname: Parker
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Janet
authors.initials: J
authors.lastname: Clarke
authors.forename: Meena
authors.initials: M
authors.lastname: Subramanyam
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D019540:Area Under Curve; D001831:Body Temperature / Q000187:drug effects; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological; D006207:Half-Life; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D016899:Interferon-beta; D007372:Interferons / Q000276:immunology / Q000494:pharmacology* / Q000633:toxicity*; D018655:Lymphocyte Count; D008253:Macaca mulatta; D015233:Models, Statistical; D019798:Neopterin / Q000097:blood; D019055:No-Observed-Adverse-Effect Level; D011092:Polyethylene Glycols / Q000494:pharmacology* / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; D019798:Neopterin; D016899:Interferon-beta; D007372:Interferons; C428112:peginterferon beta-1a