In vivo pharmacology and toxicology evaluation of polyethylene glycol-conjugated interferon beta-1a.
J Pharmacol Exp Ther
; 338(3): 984-96, 2011 Sep.
Article
en En
| MEDLINE
| ID: mdl-21690216
ABSTRACT
Human interferon (IFN) ß 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 ß-1a (PEG-IFN ß-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 ß-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 ß-1a and PEG-IFN ß-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 ß-1a showed greater exposure, longer half-life, lower clearance, and reduced volume of distribution than unmodified IFN ß-1a. Consistent with the pharmacology of type I IFNs, PEG-IFN ß-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 ß-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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Polietilenglicoles
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Interferones
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Antineoplásicos
Tipo de estudio:
Prognostic_studies
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Risk_factors_studies
Límite:
Animals
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Humans
Idioma:
En
Año:
2011
Tipo del documento:
Article