Abstract
Interferon alfa-2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half-life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG-modified interferon alfa-2a showed a greater than twofold increase in the circulating half-life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa-2a or PEG-interferon alfa-2a in healthy volunteers. Analysis of the pharmacokinetic-pharmacodynamic relationship suggested that the PEG-modified interferon alfa-2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.
Keywords
PharmacokineticsPharmacodynamicsImmunogenicityPharmacologyPolyethylene glycolMedicineInterferonPEG ratioIn vivoInterferon alfaDrugPEGylationAlpha interferonImmunologyChemistryImmune systemBiochemistryBiology
MeSH Terms
AdultAntiviral AgentsDose-Response RelationshipDrugDouble-Blind MethodDrug EvaluationGTP-Binding ProteinsHalf-LifeHumansInterferon alpha-2Interferon-alphaMaleModelsChemicalMyxovirus Resistance ProteinsPolyethylene GlycolsProtein BiosynthesisRecombinant ProteinsTime Factors
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Publication Info
- Year
- 1996
- Type
- article
- Volume
- 59
- Issue
- 6
- Pages
- 636-646
- Citations
- 85
- Access
- Closed
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Cite This
Keith Nieforth,
R Nadeau,
Indravadan H. Patel
et al.
(1996).
Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.
Clinical Pharmacology & Therapeutics
, 59
(6)
, 636-646.
https://doi.org/10.1016/s0009-9236(96)90003-x
Identifiers
- DOI
- 10.1016/s0009-9236(96)90003-x
- PMID
- 8681488