Interspecies scaling of clearance and volume of distribution for digoxin-specific Fab.
Digoxin-specific Fab are recognized to be effective in the treatment of acute cardiac glycoside poisoning but no pharmacokinetic studies have been performed in human volunteers. We thus propose an allometric approach among three mammalian species to predict Fab pharmacokinetic parameters in humans. Plasma disposition of digoxin-specific Fab was studied at a 20 mg/kg i.v. dose in mice, rats, and rabbits. Fab plasma concentration was determined by a sensitive and specific radioimmunoassay. Allometric equations showed that the pharmacokinetic parameters (distribution volumes (Vc (ml) = 0.084 W0.96; Vdss (ml) = 0.24 W0.96; Vd beta (ml) = 0.55 W0.96, r2 = 1), total body clearance (Cltot (ml/hr) = 0.61 W0.67, r2 = 0.999), and terminal half-life (t 1/2 beta (hr) = 0.63 W0.29) correlated with body weight. The Fab plasma concentration-time data plotted as a complex Dedrick relationship were superimposable. Using these allometric techniques, Vdss, Vd beta, Cltot and t 1/2 beta were calculated as 10.75 liter, 24.64 liter, 17.9 ml/min, and 16 hr, respectively, for a human subject of 70 kg body weight. These values are in accordance with those previously described in digoxin-Fab-treated patients (body weight = 61 +/- 3 kg, Vd beta = 24.9 +/- 3. 7 liter; Cltot = 20.8 +/- 2.1 ml/min; t 1/2 beta = 14.3 +/- 1.8 hr). Results indicate that the primary Fab pharmacokinetic parameters can be reasonably estimated in man using pharmacokinetic data from three animal species.
Grene-Lerouge
N A
NA
Inserm U26, University of Paris V, Hôpital Fernand Widal, France.
Bazin-Redureau
M I
MI
Debray
M
M
Scherrmann
J M
JM
D000818:Animals; D004077:Digoxin / Q000276:immunology*; D006207:Half-Life; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
D007140:Immunoglobulin Fab Fragments; C050199:digoxin antibodies Fab fragments; D004077:Digoxin