Interspecies Scaling of Receptor-Mediated Pharmacokinetics and Pharmacodynamics of Type I Interferons
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To develop an integrated mechanism-based modeling approach for the interspecies scaling of pharmacokinetic (PK) and pharmacodynamic (PD) properties of type I interferons (IFNs) that exhibit target-mediated drug disposition (TMDD).
PK and PD profiles of human IFN-β1a, IFN-β1b, and IFN-α2a in humans, monkeys, rats, and mice from nine studies were extracted from the literature by digitization. Concentration-time profiles from different species were fitted simultaneously using various allometric relationships to scale model-specific parameters.
PK/PD profiles of IFN-β1a in humans and monkeys were successfully characterized by utilizing the same rate constant parameters and scaling the volume of the central compartment to body weight using an allometric exponent of 1. Concentration and effect profiles of other IFNs were also well described by changing only the affinity of the drug to its receptor. PK profiles in rodents were simulated using an allometric exponent of −0.25 for the first-order elimination rate constant, and no receptor-binding was included given the lack of cross-reactivity.
An integrated TMDD PK/PD model was successfully combined with classic allometric scaling techniques and showed good predictive performance. Several parameters obtained from one IFN can be effectively shared to predict the kinetic behavior of other IFN subtypes.
KEY WORDSallometry interferon nonlinear pharmacokinetics receptor binding target-mediated drug disposition
This work was supported, in part, by Grant GM57980 from the National Institutes of Health (D.E.M.), the Center for Protein Therapeutics, University at Buffalo, SUNY (L.K. and J.M.H.), and the University at Buffalo—Pfizer Strategic Alliance (A.K.A.). Partial results of this study were presented in a poster at the 2009 AAPS Annual Meeting in Los Angeles, CA.
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