Vf. Cosson et al., MIXED EFFECT MODELING OF SUMATRIPTAN PHARMACOKINETICS DURING DRUG DEVELOPMENT .1. INTERSPECIES ALLOMETRIC SCALING, Journal of pharmacokinetics and biopharmaceutics, 25(2), 1997, pp. 149-167
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.