TIMI-10A/B

Assessment of the clinical pharmacology of tenecteplase in humans with AMI

Evaluation of pharmacokinetics and gross safety and efficacy of TNK in 113 patients with AMI:

prolonged half-life allows for single-bolus administration,
TNK is highly fibrin specific with encouraging patency and safety profiles.

A prospective angiographic comparison of single-bolus tenecteplase with accelerated alteplase in 886 patients:

rate of TIMI grade 3 flow at 90 minutes with tenecteplase 40 mg was comparable to that of accelerated alteplase

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Tenecteplase exhibits a biphasic disposition in the plasma. The initial disposition phase is predominant with a mean half-life of 17-24 minutes and a mean terminal half-life of 65-132 minutes. Over the clinically relevant dose range 30-50 mg investigated in TIMI 10B:

mean clearance (CL) was 105 mL/min,
mean initial volume of distribution (V1) was 4.2-6.3 L, and is weight related,
approximating plasma volume, and volume of distribution at steady state was 6.1-9.9 L, suggesting limited extravascular distribution or binding.

The graphic illustrates the time-dependent plasma concentrations of alteplase and tenecteplase. The plasma concentration after a single bolus of tenecteplase was higher than that of alteplase given as bolus plus 90-minute infusion, but the area under the curve was similar to that of alteplase.

TIMI 10B: Pharmacokinetics of TNK-t-PA

TIMI 10B: Fibrin specificity of TNK

Tenecteplase has a far less effect on systemic coagulation factors than alteplase, because it is more fibrin specific. There was a 5-10% drop in fibrinogen over the first six hours after administration of tenecteplase, compared with a 40% drop after alteplase. The fall of plasminogen was only 10-15% after tenecteplase, compared to a 50% drop after alteplase.

Patency (TIMI grade 2/3 flow) at 90 min was 76.8-88.2% for tenecteplase and 81.7% for alteplase, the lower rate with 30 mg tenecteplase was the only significant difference. The rate of TIMI grade 3 flow was 62% for doses of 0.5 mg/kg and higher, but was 51-54% at doses lower than this (p=0.028 across quintiles of weight-corrected dose of TNK).