MIXED EFFECT MODELING OF SUMATRIPTAN PHARMACOKINETICS DURING DRUG DEVELOPMENT .1. INTERSPECIES ALLOMETRIC SCALING

Allometric scaling is an empirical examination of the relationships be tween the pharmacokinetic parameters and size (usually body weight), b ut it can also involve brain weight for metabolized drug. Through all species, the protein binding of sumatriptan is similar (14-16%), and i ts metabolic pathway undergoes extensive oxidative deamination involvi ng the monoamine oxidase A isoenzyme. These similarities across specie s suggested the possible relevance of an allometric analysis. Toxicoki netic data were collected from rats, pregnant rabbits, and dogs in ani mal pharmacokinetic studies where sumatriptan was administered intrave nously to the animals at doses of 5 mg/kg, 0.25 mg/kg, and 1 mg/kg, re spectively. Animal data were pooled and analyzed in one step using a m ixed effect modeling (population) approach. The kinetic parameters pre dicted in any species were close to the observed values by species. 77 L/hr vs. 80 L/hr in man for total clearance, 137 L. vs. 119 L, for di stribution volume at steady state. The value of the mix-ed effect mode ling approach compared to the two-step method was demonstrated especia lly with the possibility of including covariates to describe the statu s of animal (e.g., pregnancy) in the model. Knowledge of the animal ki netics, dynamics, and metabolism of a drug contributes to optimal and expeditious development. Valuable information for the design of the fi rst-dose-in-man study may expeditious more creative data analysis base d on all the information collected during the preclinical and ongoing nonclinical evaluation of a new drug.