Retavase Pharmacology, Pharmacokinetics, Studies, Metabolism - Reteplase

Retavase Pharmacology, Pharmacokinetics, Studies, Metabolism - Reteplase

CLINICAL PHARMACOLOGY

General

RetavaseŽ is a recombinant plasminogen activator which catalyzes the cleavage of endogenous plasminogen to generate plasmin. Plasmin in turn degrades the fibrin matrix of the thrombus, thereby exerting its thrombolytic action. ^1,2 In a controlled trial, 36 of 56 patients treated for an acute myocardial infarction (AMI) had a decrease in fibrinogen levels to below 100 mg/dL by 2 hours following the administration of RetavaseŽ as a double-bolus intravenous injection (10 + 10 U) in which 10 U (17.4 mg) was followed 30 minutes later by a second bolus of 10 U (17.4 mg). ³ The mean fibrinogen level returned to the baseline value by 48 hours.

Pharmacokinetics

Based on the measurement of thrombolytic activity, RetavaseŽ is cleared from plasma at a rate of 250-450 mL/min, with an effective half-life of 13-16 minutes. RetavaseŽ is cleared primarily by the liver and kidney.

Clinical Studies

The safety and efficacy of RetavaseŽ were evaluated in three controlled clinical trials in which RetavaseŽ was compared to other thrombolytic agents. The INJECT study was designed to assess the relative effects of RetavaseŽ or the StreptaseŽ brand of Streptokinase upon mortality rates at 35 days following an AMI. The other studies (RAPID 1 and RAPID 2) were arteriographic studies which compared the effect on coronary patency of RetavaseŽ to two regimens of Alteplase (a tissue plasminogen activator; ActivaseŽ in the USA and ActilyseŽ in Europe) in patients with an AMI. In all three studies, patients were treated with aspirin (initial doses of 160 mg to 350 mg and subsequent doses of 75 mg to 350 mg) and heparin (a 5,000 U IV bolus prior to the administration of RetavaseŽ, followed by a 1000 U/hour continuous IV infusion for at least 24 hours). ^3,4,5 The safety and efficacy of RetavaseŽ have not been evaluated using antithrombotic or antiplatelet regimens other than those described above.

RetavaseŽ (10 + 10 U) was compared to Streptokinase (1.5 million units over 60 minutes) in a double-blind, randomized, European study (INJECT), which studied 6,010 patients treated within 12 hours of the onset of symptoms of AMI. To be eligible for enrollment, patients had to have chest pain consistent with coronary ischemia and ST segment elevation, or a bundle branch block pattern on the EKG. Patients with known cerebrovascular or other bleeding risks or those with a systolic blood pressure >200 mm Hg or a diastolic blood pressure >100 mm Hg were excluded from enrollment. The results of the primary endpoint (mortality at 35 days), six month mortality and selected other 35 day endpoints are shown in Table 1 for patients receiving study medications.

For morality, stroke and the combined outcome of mortality or stroke, the 95% confidence intervals in Table 1 reflect the range within which the true difference in outcomes probably lies and includes the possibility of no difference. The incidences of congestive heart failure and of cardiogenic shock were significantly lower among patients treated with RetavaseŽ.

The total incidence of stroke was similar between the groups. However, more patients treated with RetavaseŽ experienced hemorrhagic strokes than patients treated with Streptokinase. An exploratory analysis indicated that the incidence of intracranial hemorrhage was higher among older patients or those with elevated blood pressure. The incidence of intracranial hemorrhage among the 698 patients treated with RetavaseŽ who were older than 70 years was 2.2%. Intracranial hemorrhage occurred in 8 of the 332 (2.4%) patients treated with RetavaseŽ who had an initial systolic blood pressure >160 mm Hg and in 15 of the 2,629 (0.6%) RetavaseŽ patients who had an initial systolic blood pressure <160 mm Hg.

Two arteriographic studies (RAPID 1 and RAPID 2) were performed utilizing open-label administration of the study agents and a blinded review of the arteriograms. In RAPID 1, patients were treated within 6 hours of the onset of symptoms, and in RAPID 2, patients were treated within 12 hours of the onset of symptoms. Both studies evaluated coronary artery perfusion through the infarct-related artery 90 minutes after the initiation of therapy as the primary endpoint. Some patients in each study also had perfusion through the infarct-related artery evaluated at 60 minutes after the initiation of therapy. In RAPID 1, RetavaseŽ (in doses of 10 + 10 U, 15 U, or 10 + 5 U) was compared to a 3 hour regimen of Alteplase (100 mg administered over 3 hrs). In RAPID 2, RetavaseŽ (10 + 10 U) was compared to an accelerated regimen of Alteplase (100 mg administered over 1.5 hrs). The percentages of patients with partial or complete flow (TIMI grades 2 or 3) and complete flow (TIMI grade 3), are shown along with ventricular function assessments in Table 2. The follow-up arteriogram was performed at a median of 8 (RAPID 1) and 5 (RAPID 2) days following the administration of the thrombolytics. In RAPID 1 the best patency results were obtained with the 10 + 10 U dose. In RAPID 2, the percentage of patients with partial or complete flow and the percentage of patients with complete flow was significantly higher with RetavaseŽ than with Alteplase at 90 minutes after the initiation of therapy. In both clinical trials the reocclusion rates were similar for RetavaseŽ and Alteplase. The relationship between coronary artery patency and clinical efficacy has not been established.

Approximately 70% (RAPID 1) and 78% (RAPID 2) of the patients in the arteriographic studies underwent optional arteriography at 60 minutes following the administration of the study agents. In both trials the percentage of patients with complete flow at 60 minutes was significantly higher with RetavaseŽ than with Alteplase. Neither RAPID clinical trial was designed nor powered to compare the efficacy or safety of RetavaseŽ and Alteplase with respect to the outcomes of mortality and stroke.