Animal pharmacokinetics and interspecies scaling from animals to man of lamifiban, a new platelet aggregation inhibitor.
Relating pharmacokinetic information obtained in animal species to man (interspecies scaling) can play an important role in enabling understanding of the differences and similarities between species, and helping to predict the kinetic profile of a new compound in man. Interspecies scaling techniques have been applied to lamifiban (Ro 44-9883), a new selective and potent nonpeptidic inhibitor of human glycoprotein IIb-IIIa intended for use in clinical treatment of, for example, acute coronary syndrome. The pharmacokinetic profile of lamifiban in man was predicted from animal data (in rats, dogs and cynomolgus monkeys) by using allometric scaling and concentration-time transformations. These extrapolations for lamifiban were performed prospectively, to help design the first pharmacokinetic studies in man. The approach based on equivalent time was preferred for our prospective predictions, in view of the high values found for the allometric exponents. Using allometric scaling, clearance (CL), half-life (t1/2) and volume of distribution (Vd) were overestimated by approximately two- to fourfold. Compared with allometric scaling, the transformation based on equivalent time improved the prediction for all human pharmacokinetic parameters. For t1/2 and CL, the observed values for man were within the range predicted from the various animal species. Of the individual animal species, the cynomolgus monkey gave the most reliable predictions of these two parameters, as well as accurately predicting the Vd value.
Lave
T
T
Hoffmann-LaRoche, Basel, Switzerland.
Saner
A
A
Coassolo
P
P
Brandt
R
R
Schmitt-Hoffmann
A H
AH
Chou
R C
RC
D000085:Acetates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D006207:Half-Life; D007275:Injections, Intravenous; D008252:Macaca fascicularis; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D000085:Acetates; D010975:Platelet Aggregation Inhibitors; D014443:Tyrosine; C084062:lamifiban