PRODUCT MONOGRAPH IMITREX DF IMITREX ... - GlaxoSmithKline

Active tubular secretion of sumatriptan occurred in the kidneys of rats and rabbits but notin the dog, where clearance was primarily metabolic.The repeat-dose pharmacokinetics of sumatriptan in the mouse, rat, rabbit and dog weregenerally consistent with the single-dose data. Plasma levels attained in these speciesshowed that sumatriptan concentrations were linearly-related to oral doses up to160 mg/kg in mice, 200 mg/kg in rats (subcutaneous doses up to 25 mg/kg), 400 mg/kg inrabbits and 100 mg/kg in dogs (subcutaneous doses up to 24 mg/kg).Following intranasal administration to the rat or dog, plasma concentrations ofsumatriptan peaked at approximately 30 minutes; in the monkey it peaked at 15 minutes.A second peak was observed in some animals at 90-120 minutes, suggesting absorptionof a swallowed portion of the dose.The maximum concentrations of sumatriptan detected in plasma following oral orsubcutaneous administration to dogs were 35- and 75-fold higher, respectively, than weremeasured in human plasma following standard therapeutic doses.There was no evidence of accumulation or enzyme inhibition/induction in any of thespecies studied.Radioactive drug-related material was widely distributed throughout the body followingboth oral and intravenous administration of radiolabelled sumatriptan. Transfer into thecentral nervous system was limited.Drug-related material was cleared rapidly from all tissues with the exception of the eye inwhich it appeared to be bound to the melanin in the uveal tract.The binding of sumatriptan to plasma proteins over the concentration range 10 to1000 ng/mL was low, 21% or less, in all species studied. Erythrocyte-associated 14 C-GR43175 was reversibly bound.Placental transfer studies in rat and rabbit showed that in both species the fetuses wereexposed to low levels of drug-related material. Sumatriptan and drug-related materialwere secreted into the milk of lactating rats and were present at higher concentrationsthan those seen in maternal plasma.Following oral administration to the rabbit and dog, and intravenous administration to thedog, and intranasal administration to the rat and dog, the indole acetic acid derivativeGR49336 was the major metabolite formed.This metabolite was also a major component in the urine of rats after both oral andintravenous and intranasal administration and in rabbits after intravenous administration,indicating that oxidative deamination is the major metabolic pathway in all animalspecies studied.October 21, 2014Page 32 of 58