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Purpose.
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.
Methods.
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.
Results.
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.
Conclusions.
The PEG-modification of IFN-β 1a provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.
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Abbreviations
- Ap:
-
amount of drug in central compartment
- Asc:
-
amount of drug in SC administration site
- At:
-
amount of drug in non-specific binding compartment
- k′:
-
first-order rate constant of drug absorption to and elimination from central compartment
- k12:
-
first-order rate constant of drug distribution from central to nonspecific binding compartment
- A21:
-
first-order rate constant of drug distribution from nonspecific binding to central compartment
- kin:
-
zero-order rate constant of neopterin production
- kout:
-
first-order rate constant of neopterin elimination
- N:
-
neopterin plasma concentration
- N0:
-
baseline or time-zero neopterin concentration
- SC50:
-
drug concentration producing 50% of Smax
- Smax:
-
capacity factor for drug stimulation of kin
- τ:
-
pharmacodynamic time-lag
- V/F:
-
volume of distribution of PEG-IFN-β 1a corrected for bioavailability
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Mager, D., Neuteboom, B. & Jusko, W. Pharmacokinetics and Pharmacodynamics of PEGylated IFN-β 1a Following Subcutaneous Administration in Monkeys. Pharm Res 22, 58–61 (2005). https://doi.org/10.1007/s11095-004-9009-z
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DOI: https://doi.org/10.1007/s11095-004-9009-z