, Volume 41, Issue 15, pp 1229-1245
Date: 14 Oct 2012

Pharmacokinetics and Pharmacodynamics of Tenecteplase in Fibrinolytic Therapy of Acute Myocardial Infarction

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Abstract

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 V1 was 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 AUC2–90 exceeded 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.