Valirie Cosson, Eliane Fuseau, Ph D, Constantin Efthymiopoulos, Alan Bye, Ph D
Clinical Pharmacokinetics Department, Glaxo Research and Development Limited, Greenford UK
There is no doubt that the knowledge of the animal kinetics, dynamics and metabolism of a drug contributes to optimal and expeditious development. Studies of pharmacokinetics and drug metabolism in animals form an integral part of the preclinical and ongoing nonclinical evaluation of a new drug. These data are used to predict starting and maximal doses in human studies and when evaluated in conjunction with the data obtained in human pharmacokinetic studies, serve as an index for animal to human comparisons and extrapolations. Methods based on non linear mixed effect modelling have proved useful for interspecies allometric scaling using preclinical data. The allometric technique works best for drugs eliminated renally, for highly cleared drugs and drugs cleared by metabolic reactions not involving mixed-function oxidase system. Sumatriptan is in the category regarded as unsuitable for allometric scaling: the protein binding is similar through all the species (11-21%), in all species the majority of the absorbed dose is renally excreted, predominantly as the indole acetic acid metabolite and unchanged drug. The renal clearance (CLR) varies in relative importance being highest in rats and rabbits, representing 40% of total plasma clearance (CLT) and lowest in humans, representing 20% of total plasma clearance. The metabolic pathway of Sumatriptan undergoes extensive oxidative deamination involving the monoamine oxidase A isoenzyme. Data were collected from rats, rabbits and dogs in toxicokinetic studies where sumatriptan was administered intravenously to the animals at the respective doses of 5mg/kg, 0.25mg/kg and 1 mg/kg. Allometric scaling using individual data (with a variable number of concentration-time points across species) was performed using NONMEM. A surprisingly reasonable fit of all animal species data was obtained. However, prediction of the total clearance in man was underestimated, reflecting the known different ratio of CLR/CLT in human compared to the animal species tested. Thus, the use of the predicted clearance would have been safe in designing the first administration to man. This exercise has renewed our confidence in using NONMEM for the allometric scaling of other metabolically extracted drugs.