Pharmacokinetics and toxicity of high doses of antibody Fab fragments in rats.
The treatment of drug toxicity with drug-specific antibody fragments may, for some compounds, require very high doses of antibody fragments. To examine the feasibility of this therapeutic approach, the pharmacokinetics and toxicity of high doses of nonspecific human IgG Fab fragments were studied in rats. Six animals received 7.5 g/kg iv Fab over 1 hr. Maximum serum Fab concentration was 42.1 +/- 9.9 mg/ml. Calculated pharmacokinetic parameters included steady state volume of distribution 0.43 +/- 0.06 liter/kg, t/2 alpha 2.4 +/- 1.4 hr, t/2 beta 16.3 +/- 2.4 hr, and systemic clearance 27.2 +/- 4.4 ml/hr/kg. Urinary excretion accounted for 31.8 +/- 7.5% of the administered dose. These values are similar to those previously reported for much lower doses (5-15 mg/kg) of digoxin-specific Fab fragments in dogs, baboons, and humans. All animals tolerated Fab infusion without changes in blood pressure, heart rate, or electrocardiogram. The serum creatinine concentration and urinary protein excretion were unchanged 1 week after Fab administration. One animal developed a self-limited respiratory illness 1 week after Fab administration, probably because of intercurrent infection. Organ histology 2 weeks after Fab administration was normal in all animals. These data suggest that rapid iv administration of high doses of antibody Fab fragments is feasible and support the potential use of high doses of Fab fragments as a therapy for drug toxicity. Although the possibility of dose-dependent kinetics was not studied, the similarity of the pharmacokinetics of this high Fab dose in the rat to that of lower doses in other species further suggests that the rat may be a suitable species for studying Fab-drug interactions.
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D003404:Creatinine / Q000097:blood; D004591:Electrophoresis, Polyacrylamide Gel; D006334:Heart Function Tests; D007140:Immunoglobulin Fab Fragments; D008297:Male; D008970:Molecular Weight; D010599:Pharmacokinetics; D051381:Rats; D012129:Respiratory Function Tests
D000906:Antibodies; D007140:Immunoglobulin Fab Fragments; D003404:Creatinine