Human interferon beta (IFN beta) has well-established beneficial effects in treating relapsing forms of multiple sclerosis (MS) patients, but current first-line treatment requires frequent (from daily to weekly) parenteral administration. A 20 kDa polyethylene glycol conjugated IFN beta-1a (PEG-IFN beta-1a) is being developed to decrease the frequency of administration and improve patient convenience and compliance. This manuscript presents pharmacokinetic (PK) and pharmacodynamic (PD) parameters, immunogenicity, and safety of PEG-IFN beta-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 practices (GLP) were conducted. The PK of IFN beta-1a and PEG-IFN beta-1a were modeled with a 2-compartment model and the link between drug concentration and neopterin response (PD marker) was described with an indirect stimulatory model. PEG-IFN beta-1a showed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN beta-1a. Consistent with the pharmacology of Type I IFNs, PEG-IFN beta-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 beta-1a formed in almost all monkeys following 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 five weeks. The no-observed-adverse-effect-level (NOAEL) was determined to be 100 µg/kg (11 MIU/kg), the highest dose tested.
- Received February 17, 2011.
- Revision received June 17, 2011.
- Accepted June 17, 2011.
- The American Society for Pharmacology and Experimental Therapeutics