Pharmacokinetics and pharmacodynamics of tenecteplase in fibrinolytic therapy of acute myocardial infarction.
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 V(1) 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 V(1). Total bodyweight explained 19% of the variability in CL and 11% of the variability in V(1), 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 AUC(2-90) exceeded 320 microg.min/ml, corresponding to an average plasma concentration of 3.6 microg/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.
Tanswell
Paul
P
Department of Pharmacokinetics and Metabolism, Boehringer Ingelheim Pharma KG, Birkendorfer Strasse 65, 88397 Biberach, Germany. paul.tanswell@bc.boehringer-ingelheim.com
Modi
Nishit
N
Combs
Dan
D
Danays
Thierry
T
D000208:Acute Disease; D000818:Animals; D001711:Biotransformation; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D000077785:Tenecteplase; D015912:Thrombolytic Therapy; D014018:Tissue Distribution; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D000077785:Tenecteplase