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.
Footnotes
This work was supported by Biogen Idec Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.180661.
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ABBREVIATIONS:
- IFN
- interferon
- PEG
- polyethylene glycol
- PEGylated
- PEG-conjugated
- PEGylation
- PEG conjugation
- AUC
- area under the curve
- CL
- clearance
- MS
- multiple sclerosis
- NCA
- noncompartmental analysis
- PD
- pharmacodynamic
- PK
- pharmacokinetic
- BAb
- binding antibody
- NAb
- neutralizing antibody
- ELISA
- enzyme-linked immunosorbent assay
- HRP
- horseradish peroxidase
- %CV
- coefficient of variation
- Ka
- absorption rate
- Ke
- elimination rate
- SYN
- baseline synthesis rate
- KTR
- first-order rate constant exiting transit compartment
- NEOP
- neopterin concentration
- BSL
- baseline concentration before dosing
- MTT
- mean time delay in the transit compartment
- VPC
- visual predictive check
- MIU
- 1 million international units.
- Received February 17, 2011.
- Accepted June 17, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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