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

Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis
J P HéraultJ M Herbert

Abstract

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...Continue Reading

Citations

Sep 7, 2011·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yeamin HuhMeihau Rose Feng
Mar 9, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Eric D BoittierDeirdre R Coombe
Sep 10, 2003·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·P PottierN Passuti
Oct 22, 2020·TH Open : Companion Journal to Thrombosis and Haemostasis·Francesco Marongiu, Doris Barcellona

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