Pharmacokinetics and pharmacodynamics of PEGylated IFN-beta 1a following subcutaneous administration in monkeys.
OBJECTIVE
To characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of a new polyethylene glycol (PEG) conjugate formulation of interferon (IFN)-beta la following subcutaneous (SC) administration in monkeys.


METHODS
Single SC injections of 0.3, 1, and 3 million international units (MIU)/kg of PEG-IFN-beta 1a were administered to 3 groups of cynomolgus monkeys (n = 4 each). Plasma concentrations of drug and neopterin, a classic biomarker for IFN-beta PD, were measured at various time-points after dosing. PK/PD profiles were described by noncompartmental methods and pooled data by an integrated mathematical model, where fixed and delayed concentration-time profiles were used as driving functions in an indirect stimulatory response model.


RESULTS
PEG-IFN-beta 1a was rapidly absorbed, with peak concentrations observed at about 4-5 h. Compared to previous identical SC doses of IFN-beta la, administration of 1 and 3 MIU/kg of pegylated drug resulted in 27- and 16-fold increases in area under the concentration-time curves. Neopterin concentrations followed a typical dose-dependent biphasic pattern. Pooled PD profiles were well-described by the PK/PD model, and the neopterin elimination rate (0.0190 h(-1)) is consistent with previous estimates.


CONCLUSIONS
The PEG-modification of IFN-beta la provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.
Mager
Donald E
DE
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14260, USA.
Neuteboom
Berend
B
Jusko
William J
WJ
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007279:Injections, Subcutaneous; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D008252:Macaca fascicularis; D023421:Models, Animal; D008956:Models, Chemical; D019798:Neopterin / Q000096:biosynthesis; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000096:biosynthesis
D017472:Receptors, Interleukin-1; D001613:beta 2-Microglobulin; D011092:Polyethylene Glycols; D019798:Neopterin; D016899:Interferon-beta; D015088:2',5'-Oligoadenylate Synthetase; D000068556:Interferon beta-1a