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 underst anding of the differences and similarities between species, and helpin g to predict the kinetic profile of a new compound in man. Interspecie s scaling techniques have been applied to lamifiban (Ro 44-9883), a ne w selective and potent non-peptidic inhibitor of human glycoprotein II b-IIIa intended for use in clinical treatment of, for example, acute c oronary syndrome. The pharmacokinetic profile of lamifiban in man was predicted from animal data (in rats, dogs and cynomolgus monkeys) by u sing allometric scaling and concentration-time transformations. These extrapolations for lamifiban were performed prospectively, to help des ign the first pharmacokinetic studies in man. The approach based on eq uivalent time was preferred for our prospective predictions, in view o f 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 wit h allometric scaling, the transformation based on equivalent time impr oved the prediction for all human pharmacokinetic parameters. For t1/2 and CL, the observed values for man were within the range predicted f rom the various animal species.Of the individual animal species, the c ynomolgus monkey gave the most reliable predictions of these two param eters, as well as accurately predicting the Vd value.