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 therapeutic or diagnostic uses. Preclinical pharmaceutical development studies are necessary before their use in humans. Here we propose an allometric approach among three mammalian species to predict F(ab')2 pharmacokinetic 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 i.v. in mice, rats, and rabbits. Using the allometric method, we demonstrate that the pharmacokinetic parameters that correlated with body weight were distribution volume (Vdc (ml) = 0.125 W0.87; Vdss (ml) = 0.251 W0.87; Vd beta (ml) = 0.290 W0.87, r2 = 1), total clearance (Cltot (ml/h) = 0.049 W0.53, r2 = 0.99), and terminal half-life (t1/2 beta (h) = 4.35 W0.33). The F(ab')2 plasma concentration-time data plotted as a complex Dedrick relationship were superimposable. Using these allometric techniques, Vdss, Vd beta, Cltot, and t1/2 beta were calculated as 4.12 liter, 4.78 liter, 19.07 ml/h, and 7.2 days, respectively, for a human subject of 70 kg body wt. Predicted human pharmacokinetic parameters were comparable for volume of distribution with the value reported by Hnatowich et al. (Cancer Res. 47, 6111-6117, 1987): 3.5 liter. However, the clearance was six-fold lower than values given by Hnatowich et al. (130 ml/h) and Ho et al.
Bazin-Redureau
M
M
Inserm U26, University of Paris V, Hôpital Fernand Widal, France.
Pepin
S
S
Hong
G
G
Debray
M
M
Scherrmann
J M
JM
D000818:Animals; D000997:Antivenins / Q000097:blood* / Q000494:pharmacology; D019540:Area Under Curve; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006736:Horses; D007140:Immunoglobulin Fab Fragments / Q000097:blood* / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D010599:Pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012984:Software; D013045:Species Specificity; D013997:Time Factors
D000997:Antivenins; D007140:Immunoglobulin Fab Fragments