PHARMACOKINETICS AND INTERSPECIES SCALING OF RECOMBINANT HUMAN FACTOR-VIII

Recombinant human (rh) factor VIII is a glycoprotein consisting of mul tiple polypeptides with relative mobilities (M(r)) ranging from 80,000 to 210,000. It is produced in mammalian cells. Single-dose intravenou s pharmacokinetic studies were conducted with rh factor VIII (Kogenate rh Antihemophilic Factor, Miles, Inc.) in male mice (21.0-25.8 g) and rats (252.0-254.2 g). Each species received 400 IU/kg, and blood was collected up to 12 hr (mice) or 32.5 hr (rats) post-dose. Immunoreacti ve factor VIII concentrations in plasma were quantified by a sensitive and specific ELISA. In both species, the disposition profiles were de scribed by the sum of two exponentials. The pharmacokinetics of rh fac tor VIII in mouse were as follows: clearance, 27.7 ml/hr/kg; initial v olume of distribution, 72 ml/kg; steady-state volume of distribution, 148 ml/kg; and terminal half-life, 4.1 hr. In rat, the mean estimates were as follows: clearance, 16.0 ml/hr/kg; initial volume of distribut ion, 41 ml/kg; steady-state volume of distribution, 125 ml/kg; and ter minal half-life, 5.5 hr. These pharmacokinetic parameters for rh facto r VIII in animals and human rh factor VIII pharmacokinetic parameters from the literature were evaluated to determine if the parameters can be represented by the allometric relationship, Y = aW(b), where Y is t he pharmacokinetic parameter, and W is body weight. The following allo metric relations were obtained for rh factor VIII: clearance (ml/hr)= 10.4 W-0.69, half-life (hr)= 7.5 W-0.18, initial volume of distributio n (ml) = 43.6 W-1.04, and steady-state volume of distribution (ml) = 9 9.1 W-0.84. The allometric exponents for each parameter conformed to t heory and were within the range of values commonly observed for xenobi otics and therapeutic proteins. These studies suggest that the pharmac okinetics of rh factor VIII in laboratory animals are predictive of th e disposition in humans despite the complex nature of its biological i nteractions and the chemical diversity of the purified material. (C) 1 996 Academic Press, Inc.