Pharmacokinetics and Pharmacodynamics of PEGylated IFN-β 1a Following Subcutaneous Administration in Monkeys
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To characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of a new polyethylene glycol (PEG) conjugate formulation of interferon (IFN)-β 1a following subcutaneous (SC) administration in monkeys.
Single SC injections of 0.3, 1, and 3 million international units (MIU)/kg of PEG-IFN-β 1a were administered to 3 groups of cynomolgus monkeys (n = 4 each). Plasma concentrations of drug and neopterin, a classic biomarker for IFN-β 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.
PEG-IFN-β 1a was rapidly absorbed, with peak concentrations observed at about 4–5 h. Compared to previous identical SC doses of IFN-β 1a, 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.
The PEG-modification of IFN-β 1a provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.
Key words:interferon-beta 1a neopterin pharmacodynamics pharmacokinetics polyethylene glycol
amount of drug in central compartment
amount of drug in SC administration site
amount of drug in non-specific binding compartment
first-order rate constant of drug absorption to and elimination from central compartment
first-order rate constant of drug distribution from central to nonspecific binding compartment
first-order rate constant of drug distribution from nonspecific binding to central compartment
zero-order rate constant of neopterin production
first-order rate constant of neopterin elimination
neopterin plasma concentration
baseline or time-zero neopterin concentration
drug concentration producing 50% of Smax
capacity factor for drug stimulation of kin
volume of distribution of PEG-IFN-β 1a corrected for bioavailability
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