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
Ka. Nieforth et al., 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 and therapeutics, 59(6), 1996, pp. 636-646
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 grea
ter 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. An
alysis of the pharmacokinetic-pharmacodynamic relationship suggested t
hat 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 wee
kly. These results were consistent with findings in phase TI trials, T
his study substantiates the usefulness of pharmacodynamic modeling as
a tool for the development of dose recommendations and for the early s
election of drug candidates in the drug development process.