INTERSPECIES SCALING OF CLEARANCE AND VOLUME OF DISTRIBUTION FOR HORSE ANTIVENOM F(AB')(2)

F(ab')(2) fragments are sometimes preferred to whole IgG for therapeut ic or diagnostic uses. Preclinical pharmaceutical development studies are necessary before their use in humans. Here we propose an allometri c approach among three mammalian species to predict F(ab')(2) pharmaco kinetic parameters in humans. Plasma disposition of horse antivenom F( ab')(2) fragments labeled with iodine 125 was studied at a dose of 10 mg/kg iv in mice, rats, and rabbits. Using the allometric method, we d emonstrate that the pharmacokinetic parameters that correlated with bo dy weight were distribution volume (Vd(c) (ml) = 0.125 W-0.87; Vd(ss) (ml) = 0.251 W-0.87; Vd(beta) (ml)= 0.290 W-0.87, r(2) = 1), total cle arance (CI,, (ml/h) = 0.049 W-0.53, r(2) = 0.99), and terminal half-li fe (t1/2 beta (h) = 4.35 W-0.33). The F(ab')(2) plasma concentration-t ime data plotted as a complex Dedrick relationship were superimposable . Using these allometric techniques, Vd(ss), Vd(beta), Cl-tot and t1/2 beta were calculated as 4.12 liter, 4.78 liter, 19.07 ml/h, and 7.2 d ays, respectively, for a human subject of 70 kg body wt. Predicted hum an pharmacokinetic parameters were comparable for volume of distributi on with the value reported by Hnatowich et al. (Cancer Res. 47, 6111-6 117, 1987): 3.5 liter. However, the clearance was six-fold lower than values given by Hnatowich et al. (130 mVh) and Ho ef al. (C) 1998 Acad emic Press.