PURPOSE: 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.
PURPOSE: 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 humanIFN-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.
Authors: R B Pepinsky; D J LePage; A Gill; A Chakraborty; S Vaidyanathan; M Green; D P Baker; E Whalley; P S Hochman; P Martin Journal: J Pharmacol Exp Ther Date: 2001-06 Impact factor: 4.030
Authors: Alicia M Segrave; Donald E Mager; Susan A Charman; Glenn A Edwards; Christopher J H Porter Journal: J Pharmacol Exp Ther Date: 2004-02-10 Impact factor: 4.030
Authors: Sean D McKenna; Kristin Vergilis; Antonio R N Arulanandam; Weishui Y Weiser; Roustem Nabioullin; Mark A Tepper Journal: J Interferon Cytokine Res Date: 2004-02 Impact factor: 2.607
Authors: Andreas M Hohlbaum; Hendrik Gille; Stefan Trentmann; Maria Kolodziejczyk; Barbara Rattenstetter; Coby M Laarakkers; Galina Katzmann; Hans Jürgen Christian; Nicole Andersen; Andrea Allersdorfer; Shane A Olwill; Bernd Meibohm; Laurent P Audoly; Dorine W Swinkels; Rachel P L van Swelm Journal: Br J Pharmacol Date: 2018-02-23 Impact factor: 8.739