Pharmacokinetics and Pharmacodynamics of Tenecteplase in Fibrinolytic Therapy of Acute Myocardial Infarction
作者:
Paul Tanswell,
Nishit Modi,
Dan Combs,
Thierry Danays,
期刊:
Clinical Pharmacokinetics
(ADIS Available online 2002)
卷期:
Volume 41,
issue 15
页码: 1229-1245
ISSN:0312-5963
年代: 2002
出版商: ADIS
关键词: Myocardial infarction;Plasminogen activators, pharmacodynamics;Tenecteplase, pharmacodynamics
数据来源: ADIS
摘要:
Tenecteplase is a novel fibrinolytic protein bioengineered from human tissue plasminogen activator (alteplase) for the therapy of acute ST-segment elevation myocardial infarction. Specific mutations at three sites in the alteplase molecule result in 15-fold higher fibrin specificity, 80-fold reduced binding affinity to the physiological plasminogen activator inhibitor PAI-1 and 6-fold prolonged plasma half-life (22 vs 3.5 minutes). Consequently, tenecteplase can be administered as a single intravenous bolus of 30−50mg (0.53 mg/kg bodyweight) over 5−10 seconds, in contrast to the 90-minute accelerated infusion regimen of alteplase.Tenecteplase plasma concentration-time profiles have been obtained from a total of 179 patients with acute myocardial infarction. Tenecteplase exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17−24 minutes, and the mean terminal half-life was 65−132 min. Over the clinically relevant dose range of 30−50mg, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution V1was 4.2−6.3L, approximating plasma volume, and volume of distribution at steady state was 6.1−9.9L, suggesting limited extravascular distribution or binding. Bodyweight and age were found to influence significantly both CL and V1. Total bodyweight explained 19% of the variability in CL and 11% of the variability in V1, and a 10kg increase in total bodyweight resulted in a 9.6 ml/min increase in CL. This relationship aided the development of a rationale for the weight-adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in CL.The percentage of patients who achieved normal coronary blood flow was clearly related to AUC. More than 75% of patients achieved normal flow at 90 minutes after administration when their partial AUC2−90exceeded 320 μg • min/ml, corresponding to an average plasma concentration of 3.6 μg/ml. Systemic exposure to tenecteplase at all times after bolus administration of 30−50mg was higher than for alteplase 100mg.Tenecteplase has demonstrated equivalent efficacy and improved safety compared with the current gold standard alteplase in a large mortality trial (ASSENT-2). This suggests that the reduced clearance, greater fibrin specificity and higher PAI-1 resistance of tenecteplase allow higher plasma concentrations and thus a more rapid restoration of coronary patency to be attained, while providing a reduction in major non-cerebral bleeding events.
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