Effect of Antivenom on Venom Pharmacokinetics in Experimentally Envenomed Rabbits: Toward an Optimization of Antivenom Therapy
- Gilles Rivière1,
- Valérie Choumet1,
- Françoise Audebert1,
- Alain Sabouraud2,
- Marcel Debray3,
- Jean-Michel Scherrmann2 and
- Cassian Bon1
- 1Unité des Venins, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15 (G.R., V.C., F.A., C.B.), 2Unité INSERM, Hôpital Fernand Widal, 200 rue du Faubourg Saint-Denis, 75010 Paris (A.S., J.M.S.), and 3Laboratoire de Biomathématiques, Université Paris 5, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l’Observatoire, 75006 Paris (M.D.), France
Abstract
Antivenomous immunotherapy is still used empirically. To improve the efficacy and safety of immunotherapy, we studied the effects of administering antivenom antibodies (F(ab′)2) on the pharmacokinetics of the Vipera aspis venom in rabbits. Free venom levels were measured by enzyme-linked immunosorbent assay and total concentrations were quantified by measuring the radioactivity of trichloroacetic acid-precipitable radioiodinated venom. The intravenous infusion of 125 mg of antivenom 7 h after intramuscular injection with 700 μg·kg−1 of V. aspis venom produced a redistribution of the venom antigens from the extravascular to the vascular space. Moreover, antivenom antibodies were able to neutralize the totality of venom antigens in the vascular space, because no free plasma venom was detectable by enzyme-linked immunosorbent assay within 15 min after antivenom injection. Similar effects were obtained after injection of 25 mg of antivenom; however, the venom was only partially neutralized with lower doses (5 and 2.5 mg). We further established that intravenous injection is the most efficient route for antivenom administration, and we examined the effects of early and late immunotherapy. Finally, the efficacy of Fab antibodies was compared with that of F(ab′)2; the plasma redistribution and the immunoneutralization of the venom were lower than those induced after injection of the same dose of F(ab′)2. The difference between the effects of F(ab′)2 and Fab could be explained by the differential pharmacokinetics of the two fragments.
Footnotes
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Send reprint requests to: Dr. Cassian Bon, Unité des Venins, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris, France.
- Abbreviations:
- AUC
- area under the curve
- AUMC
- area under the mean curve
- BSA
- bovine serum albumin
- ELISA
- enzyme-linked immunosorbent assay
- HMWP
- high molecular weight protein
- LMWP
- low molecular weight polypeptide
- PBS
- phosphate buffer saline
- TCA
- trichloroacetic acid
- Vdss
- volume of distribution at steady state
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- Received July 8, 1996.
- Accepted December 9, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
