Interspecies scaling of receptor-mediated pharmacokinetics and pharmacodynamics of type I interferons.
OBJECTIVE
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).


METHODS
PK and PD profiles of human IFN-beta1a, IFN-beta1b, and IFN-alpha2a 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.


RESULTS
PK/PD profiles of IFN-beta1a 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.


CONCLUSIONS
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.
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Amherst, New York, 14260, USA.
Leonid
L
Kagan
Anson K
AK
Abraham
John M
JM
Harrold
Donald E
DE
Mager
D000465:Algorithms; D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001835:Body Weight / Q000502:physiology; D002522:Chlorocebus aethiops; D006207:Half-Life; D006801:Humans; D007370:Interferon Type I / Q000493:pharmacokinetics*; D000077190:Interferon alpha-2; D000068576:Interferon beta-1b; D016898:Interferon-alpha / Q000493:pharmacokinetics; D016899:Interferon-beta / Q000493:pharmacokinetics; D051379:Mice; D015233:Models, Statistical; D051381:Rats; D017207:Rats, Sprague-Dawley; D017471:Receptors, Interferon / Q000378:metabolism*; D011994:Recombinant Proteins; D013045:Species Specificity
D000998:Antiviral Agents; D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D017471:Receptors, Interferon; D011994:Recombinant Proteins; D000068576:Interferon beta-1b; D016899:Interferon-beta