A comparison of the pharmacokinetics of antithrombin derived from human plasma and from transgenic goats and the prevention of sepsis in an animal model.
Antithrombin (AT) is the principal inhibitor of thrombin and other serine proteases of the coagulation cascade. AT has previously been prepared from human plasma (hpAT), and a transgenic variant from goat milk (tgAT) is now available. Two open-label, parallel pharmacokinetic studies in rats (n=18) and rabbits (n=18) compared plasma concentrations of hpAT and tgAT following intravenous administration; the efficacy of the two preparations in prolonging survival from bacterial-induced sepsis was compared in two open-label, randomised, placebo-controlled studies in rats (n=266). Maximum plasma concentrations were approximately dose-proportional and were similar for both hpAT and tgAT. The elimination of tgAT was faster than hpAT, and the t(1/2) of hpAT was longer than that of tgAT in both rats (0.85-1.92 h versus 0.17-0.73 h) and rabbits (19-38 h versus 1.5-2.2 h). Correspondingly, tgAT showed a lower area under the curve, mean residence time, pharmacokinetic response to dosing and a higher clearance rate. In a meta-analysis of the efficacy studies, the overall hazard ratio for death was 1.36 (tgAT:hpAT; p=0.06; 95% CI 0.99-1.86). HpAT and tgAT have differing pharmacokinetic properties in pre-clinical studies. Further research is necessary to establish whether this translates into efficacy differences in vivo and in the clinical therapy of sepsis.
Department of Pharmacology and Toxicology, CSL Behring GmbH, Marburg, Germany. Gerhard.Dickneite@cslbehring.com
Gerhard
G
Dickneite
D000818:Animals; D030801:Animals, Genetically Modified; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006041:Goats; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D011817:Rabbits; D011897:Random Allocation; D051381:Rats; D018805:Sepsis / Q000517:prevention & control*; D015996:Survival Rate
D000991:Antithrombins