COMPARATIVE KINETICS OF SEMATILIDE IN 4 SPECIES

The goals of this retrospective study with the novel class III antiarr hythmic sematilide HCl were to investigate: a) whether there existed i nterspecies correlations and b) whether reliable animal-to-human predi ctions were possible for the main pharmacokinetics parameters. Informa tion on plasma concentrations after intravenous administration was ava ilable in rats, rabbits, dogs, and humans. Except for the rabbit, data on the urinary amounts of drug excreted were also available in these species. The drug concentrations in plasma and urine were assayed by a specific HPLC method with UV or electrochemical detection or liquid s cintillation spectrometry. In the interspecies correlations and in the animal-to-human predictions, an allometric approach was used with log -log linear regressions of the pharmacokinetic parameters steady-state volume of distribution (V(ss)), total clearance (CL), mean residence time (t), and terminal disposition half life (t1/2lambdaz) on body wei ght The results showed that significant interspecies correlations exis t for the tested in vivo pharmacokinetic parameters for sematilide. Re liable animal-to-human predictions with errors < 60% were found for V( ss), CL, t1/2lambdaz, and t. In rats, dogs, and humans, sematilide's r enal elimination includes glomerular filtration and net tubular secret ion. The relative contributions of the renal mechanisms are similar in all three species studied. There were no important species difference s observed in the in vitro determined parameters, fraction unbound in plasma, and blood-to-plasma concentration ratio between rats, dogs, an d humans.