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: Xiao Hu, Kenneth Olivier, Evelyne Polack, Mary Crossman, Katie Zokowski, Robert S Gronke, Suezanne Parker, Zhaoyang Li, Ivan Nestorov, Darren P Baker, Janet Clarke, Meena Subramanyam
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 338 Issue 3 Pg. 984-96 (Sep 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21690216 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Polyethylene Glycols
• Neopterin
• Interferon-beta
• Interferons
• peginterferon beta-1a

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Area Under Curve
• Body Temperature (drug effects)
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay
• Feedback, Physiological
• Half-Life
• Humans
• Injections, Intramuscular
• Injections, Subcutaneous
• Interferon-beta
• Interferons (immunology, pharmacology, toxicity)
• Lymphocyte Count
• Macaca mulatta
• Models, Statistical
• Neopterin (blood)
• No-Observed-Adverse-Effect Level
• Polyethylene Glycols (pharmacology, toxicity)