Jp. Herault et al., PHARMACOKINETIC STUDY OF 3 SYNTHETIC AT-BINDING PENTASACCHARIDES IN VARIOUS ANIMAL SPECIES EXTRAPOLATION TO HUMANS, Blood coagulation & fibrinolysis, 8(3), 1997, pp. 161-167
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 b
een evaluated. The dissociation constants (Kd) for AT of the three spe
cies 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 a
nti-factor Xa activities were determined in rats, rabbits and baboons.
An apparent correlation could be demonstrated between half-lives of e
limination and the corresponding Kd for AT in rats and rabbits whereas
in baboons, such a correlation was not found. These results showed th
at despite Kd values ten times lower for 32701 than for SP, both compo
unds showed close PK parameters in baboons whereas the very low Kd val
ue for 80027 was associated with an extended terminal half-life in thi
s species. The predicted human PK parameters were determined using an
allometric model: an empirical approach based on the integration of da
ta obtained in various animal species which allows the extrapolation t
o 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 kn
owledge of duration of activity is pivotal for appropriate design of p
hase I clinical studies of anti-Xa oligosaccharides, allometry appears
to be an interesting tool to predict the duration of action of such c
ompounds in man.