TY - JOUR T1 - In Vivo Pharmacology and Toxicology Evaluation of Polyethylene Glycol-Conjugated Interferon β-1a JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 984 LP - 996 DO - 10.1124/jpet.111.180661 VL - 338 IS - 3 AU - Xiao Hu AU - Kenneth Olivier AU - Evelyne Polack AU - Mary Crossman AU - Katie Zokowski AU - Robert S. Gronke AU - Suezanne Parker AU - Zhaoyang Li AU - Ivan Nestorov AU - Darren P. Baker AU - Janet Clarke AU - Meena Subramanyam Y1 - 2011/09/01 UR - http://jpet.aspetjournals.org/content/338/3/984.abstract N2 - 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. ER -