Current clinical use of reteplase for thrombolysis - A pharmacokinetic-pharmacodynamic perspective

被引:22
作者
Martin, U
Kaufmann, B
Neugebauer, G
机构
[1] Roche Diagnost GmbH, Dept Pharmacol, Penzberg, Germany
[2] Roche Diagnost GmbH, Dept Clin Pharmacol, Mannheim, Germany
关键词
D O I
10.2165/00003088-199936040-00002
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Clinical evaluation of a new thrombolytic agent should start with a dose that provides adequate efficacy and has an acceptably low bleeding risk; this results in a narrow therapeutic window at the upper end of the dose-response curve, Angiographic patency of the infarct-related artery is still the clinical surrogate end-point for mortality in phase II dose-ranging studies. There is experimental and clinical evidence that the area under the concentration-time curve (AUC) for plasminogenolytic activity of a thrombolytic agent is positively correlated with patency of the infarct-related artery, Dose-ranging studies of the novel recombinant plasminogen activator reteplase in healthy volunteers enabled computation of a linear regression curve by which a clinical starting dose could be calculated for an adapted target AUC that would be clinically effective. Pharmacokinetic analysis also revealed that the half-life of reteplase is 4 times longer than that of the reference thrombolytic alteplase, thus allowing bolus injection, The suggested single bolus starting dose of 10U was supported by results from studies in a canine model of coronary thrombolysis, The feedback of insufficiently high patency rates compared with the increased efficacy of front-loaded and accelerated alteplase demanded optimisation strategies for reteplase, Animal experiments suggested that a double bolus regimen of reteplase would be preferable to doubling the single bolus dose. Pharmacokinetic modelling suggested a time interval of 30 min between the 2 bolus injections. Selection of the tested double bolus regimens was conservative and empirical. First, the previously tested single bolus of 15U was divided to 10 + 5U; secondly, the second bolus dose was increased to IOU. This strategy proved to be successful. The current dosage recommendation for reteplase is a double bolus intravenous injection of 10 + 10U, each over 2 min, 30 min apart. This produces a reduction in mortality in patients with acute myocardial infarction that is equivalent to that produced by front-loaded and accelerated infusion of alteplase.
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页码:265 / 276
页数:12
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