Pharmacokinetic study of three synthetic AT-binding pentasaccharides in various animal species-extrapolation to humans.

: The 'synthetic pentasaccharide', SR 90107A/Org 31540 (SP) representing the minimal AT-binding sequence of heparin is a catalyst of factor Xa inhibition. Affinity of SP, Sanorg 32701 (32701) and SR 80027 (80027), two close analogues of SP for rat, rabbit, baboon and human AT has been evaluated. The dissociation constants (Kd) for AT of the three species were in the range of 41-132, 1.4-6.2 and 2.8-4.6 nM for SP, 80027 and 32701, respectively. Comparative pharmacokinetics (PK) of their anti-factor Xa activities were determined in rats, rabbits and baboons. An apparent correlation could be demonstrated between half-lives of elimination and the corresponding Kd for AT in rats and rabbits whereas in baboons, such a correlation was not found. These results showed that despite Kd values ten times lower for 32701 than for SP, both compounds showed close PK parameters in baboons whereas the very low Kd value for 80027 was associated with an extended terminal half-life in this species. The predicted human PK parameters were determined using an allometric model: an empirical approach based on the integration of data obtained in various animal species which allows the extrapolation to humans. The values obtained for the terminal half-lives of SP, 80027 and 32701 were 14.1, 88 and 6.5 h, respectively. For SP, calculation by allometry correlated well with the values observed in man. Since knowledge of duration of activity is pivotal for appropriate design of phase I clinical studies of anti-Xa oligosaccharides, allometry appears to be an interesting tool to predict the duration of action of such compounds in man.