Recomlyse Mechanism of Action

Pharmacotherapeutic group: Antithrombotic agents, enzymes. ATC code: B01AD11.
Pharmacology: Pharmacodynamics: Mechanism of action: Recomlyse is a tissue plasminogen activator (t-PA) produced by recombinant DNA technology, using an established mammalian cell line (Chinese Hamster Ovary cells).
Recomlyse is a recombinant plasminogen activator that is derived from native t-PA by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus (blood clot) and converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus.
Recomlyse has a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor compared to native t-PA.
After administration of Recomlyse, dose dependent consumption of α2-antiplasmin (the fluid- phase inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been observed.
Clinical Trials: Acute myocardial infarction: In a randomized, blinded (blinded enrollment and central evaluators were blinded), parallel, active drug-controlled, multi-center clinical trial study, ST-segment elevation patients aged 18 to 70 years old and within 12 hours of onset were patients with acute myocardial infarction were used as the research subjects to evaluate the clinical safety and effectiveness of recombinant human TNK tissue plasminogen activator for injection in patients with ST-segment elevation acute myocardial infarction.
Dosage plan: This product is administered as a single bolus intravenous injection of 16 mg, and the injection is completed in 5 to 10 seconds.
Control drug: Recombinant Human Tissue Plasminogen Activator for Injection (rt-PA), the dosage is 50 mg. First, 8 mg should be injected intravenously at a constant rate, and the remaining 42 mg should be continuously pumped intravenously within 90 minutes.
Concomitant medications and usage: Heparin: intravenous and subcutaneous heparin treatment. Before thrombolysis, a heparin pulse dose of 70 IU/kg should be injected intravenously (the total amount should not exceed 5,000 IU). After thrombolysis (within 15 minutes), continuous intravenous pumping of heparin 1,000 IU/hour should be started for a total of 24 hours. Maintain APTT at 50 to 70 seconds. If APTT still cannot reach the target when the dose is increased to 1,200 IU/hour, do not increase the heparin dose. After 24 hours of thrombolysis, low molecular weight heparin was injected subcutaneously, at a dose of 1 mg/kg, and the dose was individualized, once every 12 hours for 3 to 5 days. For patients undergoing rescue PCI, intravenous heparin pumping is usually stopped after surgery, the arterial sheath is removed after 4 hours (APTT <50 seconds), and low molecular weight heparin is injected subcutaneously at a dose of 1 mg/kg, the dose is individualized, every 12 hours Once, for 3 to 5 consecutive days.
Aspirin and clopidogrel: Before thrombolysis, take a loading dose of 300 mg of enteric-coated aspirin, then 100 to 300 mg/day for 3 to 5 days, then change to 100 mg/day for long-term use. Concomitant use of clopidogrel: Take a loading dose of 300 mg orally before thrombolysis, and then 75 mg/day starting from the next day for 1 to 6 months.
Test results: A total of 251 patients entered this experimental study, with 124 patients in the experimental group (rhTNK-tPA group) and 127 patients in the control group (rt-PA). There were 93 and 89 patients in the two groups respectively who underwent coronary angiography 90 minutes after thrombosis to evaluate the re-canalization of the coronary arteries.
Efficacy: Patients with ST-segment elevation acute myocardial infarction within 12 hours of onset were intravenously injected with 16 mg rhTNK-tPA. After 90 minutes of coronary angiography evaluation, the recovery of blood flow in the infarction-related vessels is shown in Table 1. (See Table 1.)

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After thrombolysis, the 30-day mortality rate of rhTNK-tPA and rt-PA was 3.23% and 4.72% respectively, with no obvious differences (p>0.05). 30-day re-infarction was 1.61% and 2.36% respectively, recurrence rate of myocardial ischemia was 0.81% and 0.79% respectively, target revascularization was 24.19% and 16.54% respectively, there was also no difference in occurrence rate of other complications (shock, cardiac rupture, stroke and cardiac failure etc.) (p>0.05).
Safety: Safety of 16 mg rhTNK-tPA given by intravenous injection for the treatment of ST elevation acute myocardial infarction is better compared with rt-PA, severe bleeding is 0.81% and 0.79% respectively, no other severe bleeding events existed. Occurrence rate of minor bleeding event is 29.84% and 31.45% respectively. No allergic event occurred in either group. See the detailed information in Table 4.
In addition, the incidence of serious non-hemorrhagic adverse events, including cardiogenic shock, heart failure, cardiac rupture and electro-mechanical separation, ventricular fibrillation, and cardiac rupture, was 3.23% in the rhTNK-tPA group and 3.94% in the rt-PA group respectively. Non-serious non-hemorrhagic adverse events, including increasing of transaminases, myocardial enzymes, blood lipids, blood glucose and nausea, vomiting, fever, cough, etc., were mild. Most of these adverse events were judged to be unrelated to the trial drug, but related to underlying and/or concomitant diseases, and drug combination.
Acute ischemic stroke: A multi-center, prospective, centrally randomized, open-label, end-point blinded, active drug parallel control, non-inferiority phase III clinical trial compared rhTNK-tPA (0.25 mg/kg) and rt-PA (0.9 mg/kg) in the treatment of acute ischemic stroke (onset <4.5h). A total of 1,430 patients with acute ischemic stroke within 4.5 hours of onset were enrolled and randomly assigned to the experimental group and the control group at a ratio of 1:1. The experimental group received a single bolus intravenous injection of rhTNK-tPA 0.25 mg/kg (maximum The dose does not exceed 25 mg), and the control group is rt-PA 0.9 mg/kg (10% is intravenously injected, and 90% is intravenously dripped within 1 hour). The main efficacy indicator is the proportion of patients with mRS score 0-1 points on day 90±7. The secondary efficacy evaluation indicators include the proportion of patients with mRS score 0-2 points on day 90±7, mRS grade distribution, 24±2h, 7±1d or discharge from hospital. The proportion of patients whose NIHSS score was 0-1 or whose NIHSS score improved from baseline to NIHSS ≥4 points before (whichever occurs first).
A total of 1,430 patients were enrolled, of which 705 patients in the experimental group and 696 patients in the control group completed the study. There were 1,328 subjects in the PPS set, 676 in the experimental group and 652 in the control group. Demographic characteristics were similar between groups, and baseline disease characteristics were basically comparable.
The PPS analysis group, the proportion of patients with mRS scores of 0-1 points on the 90th± 7th day of the main efficacy index of the experimental group and the control group were 62.7% (421/671) and 59.2% (380/642) respectively; based on the pre-specified. After multiple imputation of missing data according to the set analysis standards, the two groups were 63.0% and 59.1% respectively. The effective rate ratio of the two groups was 1.067 (95% CI: 0.9775, 1.1636). The lower limit of the 95% CI was greater than the non-inferiority margin. The value is 0.937, rhTNK-tPA is non-inferior to rt-PA in efficacy.
In the safety analysis population, the overall mortality rates within 90 days of the experimental group and the control group were 6.5% (46/711) and 5.0% (35/706) respectively. Other important bleeding events are listed in the table as follows. (See Table 2.)

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Pharmacokinetics: After a single intravenous dose of recombinant human TNK tissue plasminogen activator for injection in healthy subjects, there is an obvious linear relationship between the peak concentration C_max, plasma concentration as well as AUC and the administered dose. The elimination half-life (t_½) is about 147 to 224 minutes and there is no dose dependence of clearance in the therapeutic dose range. The apparent volume of distribution is 3 L to 4 L, indicating that the drug is mainly distributed in the blood and is mainly metabolized by the liver.
Literatures showed that in the treatment of patients with acute myocardial infarction, after TNKase was administrated via bolus intravenous injection, the distribution in the plasma showed two stages. Its initial half-life of being cleared from plasma was 20 to 24 minutes, and its terminal half-life was 90 to 130 minutes. Of the 104 patients administrated with TNKase, 99 had mean plasma clearance ranging from 99 to 119 mL/min. The initial distribution of the drug was related to the patient's body weight and approximates the plasma volume. Hepatic metabolism was the main clearance mechanism of TNKase.
Renal and hepatic impairment: As the kidneys do not appear to be involved in the elimination of Recomlyse, it is not expected that renal dysfunction will affect the pharmacokinetics. The effect of hepatic dysfunction on pharmacokinetics of Recomlyse in humans has not been specifically investigated.
Toxicology: Preclinical safety data: Genotoxicity: The results of the Ames test and the Chinese hamster lung cell (CHL) chromosome aberration test were negative, and the results of the mouse bone marrow micronucleus test were negative.
Studies of rhTNK-tPA in animals have demonstrated its non-mutagenicity.
Studies of rhTNK-tPA in animals have not been performed to assess the carcinogenic potential.
No obvious effects on growth and development indicators and no obvious abnormalities in embryonic growth and development were seen based on the experiments on pregnant mice and rabbits.