Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study

• Published in: Clinical toxicology (Philadelphia, Pa.) Pa.), 2018-08, Vol.56 (8), p.773-781
• Main Authors: Eddleston, Michael, Fabresse, Nicolas, Thompson, Adrian, Al Abdulla, Ibrahim, Gregson, Rachael, King, Tim, Astier, Alain, Baud, Frederic J., Clutton, R Eddie, Alvarez, Jean-Claude
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Administration, Oral; Animals; antidote; Antidotes - pharmacology; Antidotes - therapeutic use; Basic Research; Colchicine; Colchicine - blood; Colchicine - poisoning; fab fragments; Immunoglobulin Fab Fragments - blood; Immunoglobulin Fab Fragments - pharmacology; Immunoglobulin Fab Fragments - therapeutic use; Models, Animal; Swine; Swine, Miniature
• ISSN: 1556-3650; 1556-9519
• DOI: 10.1080/15563650.2017.1422510

Background: Colchicine poisoning is commonly lethal. Colchicine-specific Fab fragments increase rat urinary colchicine clearance and have been associated with a good outcome in one patient. We aimed to develop a porcine model of colchicine toxicity to study the pharmacokinetics and efficacy of ovine Fab. Methods: A Göttingen minipig critical care model was established and serial blood samples taken for colchicine and Fab pharmacokinetics, clinical chemistry, and haematology. Animals were euthanised when the mean arterial pressure fell below 45 mmHg without response to vasopressor, or at study completion. Results: Initial studies indicated that oral dosing produced variable pharmacokinetics and time-to-euthanasia. By contrast, intravenous infusion of 0.25 mg/kg colchicine over 1 h produced reproducible pharmacokinetics (AUC 0-20 343 [SD = 21] µg/L/h), acute multi-organ injury, and cardiotoxicity requiring euthanasia a mean of 22.5 (SD = 3.2) h after dosing. A full-neutralising equimolar Fab dose given 6 h after the infusion (50% first hour, 50% next 6 h [to reduce renal-loss of unbound Fab]) produced a 7.35-fold increase in plasma colchicine (AUC 0-20 2,522 [SD = 14] µg/L/h), and removed all free plasma colchicine, but did not prevent toxicity (euthanasia at 29.1 [SD = 3.4] h). Earlier administration over 1 h of the full-neutralising dose, 1 or 3 h after the colchicine, produced a 12.9-fold (AUC 0-20 4,433 [SD = 607] µg/L/h) and 6.0-fold (AUC 0-20 2,047 [SD = 51] µg/L/h) increase in plasma colchicine, respectively, absence of free plasma colchicine until 20 h, and survival to study end without marked cardiotoxicity. Conclusions: Colchicine-specific Fab given early, in equimolar dose, bound colchicine, eliciting its movement into the blood, and preventing severe toxicity. Clinical studies are now needed to determine how soon this antidote must be given to work in human poisoning.