Pharmacokinetics and pharmacodynamics of low doses of recombinant tissue plasminogen activator to establish a model for biosimilarity comparisons.

Background: Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent and essential in emergency medical care. Given recent supply shortages, the availability of biosimilar products is an urgent medical need. However, biosimilarity trials are difficult to perform in critically ill patients. Objectives: The aim of this pilot study was to investigate the pharmacokinetics and pharmacodynamics of low rt-PA doses to establish a model for testing proposed biosimilars in healthy volunteers. Methods: Eight healthy volunteers received 0.02 to 0.05 mg/kg rt-PA on 3 study days; blood samples were obtained every 4 minutes after the end of the bolus infusion to measure rt-PA antigen levels by enzyme immunoassay, and the pharmacodynamics were assessed with rotational thromboelastometry. Results: Bolus infusion of low rt-PA doses was safe and well tolerated. Maximal plasma concentrations and the area under the curve increased dose-dependently. Time-concentration curves were clearly separated between the lower and the higher doses. As expected, the half-live of rt-PA was short (4.5-5 min), and representative for therapeutic doses. The intrasubject coefficient variations were moderate (<25%). Bolus infusion of rt-PA dose-dependently shortened lysis time and lysis onset time in both dose groups and caused maximum clot lysis of 100% in all participants. Conclusion: In conclusion, the pharmacokinetics of rt-PA was dose linear and displayed limited intrasubject variability even at subtherapeutic doses. The half-life and thus clearance of rt-PA was representative of full therapeutic doses. The lysis time was shortened in a dose and time-dependent fashion and was clearly distinguishable between doses. Thus, the model appears to be suitable and sensitive to test biosimilarity.

Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin.

BACKGROUND: High platelet reactivity (HPR) under treatment with clopidogrel or aspirin is associated with adverse outcome. We aimed to investigate whether high platelet reactivity (HPR) to both aspirin and clopidogrel is a stronger predictor of adverse events compared to isolated HPR to clopidogrel or aspirin. METHODS: In this prospective cohort study platelet reactivity to adenosine diphosphate (ADP) and arachidonic acid (AA) was assessed by Multiple Electrode Aggregometry (MEA) in 403 patients undergoing percutaneous coronary intervention. The rates of the composite of cardiac adverse events (acute coronary syndrome, stent thrombosis, stroke, death and revascularization) were recorded during 12-month follow-up. RESULTS: The composite endpoint of cardiovascular adverse events occurred more often in patients with high platelet reactivity (HPR) to both agonists ADP and AA (37.5%) than in those with isolated HPR to ADP (33.3%), AA (25.6%) or without any HPR (18.6%; p=0.003). Classification tree analysis indicated that any HPR emerged as an independent predictor influencing outcome, which was associated with a 1.75 higher risk of cardiac adverse events (OR=1.75: 95%CI=1.1-2.9). Interestingly, the predictive value of HPR tended to be greater among patients with diabetes mellitus (OR=2.18; 95%CI=1.20-3.95). C-reactive protein and diabetes mellitus were independent predictors of high platelet reactivity to both agonists. CONCLUSIONS: Dual low responsiveness to clopidogrel and aspirin is a strong predictor of cardiac adverse events, especially in patients with diabetes mellitus, which underlines the need for personalized antiplatelet treatment.

Angiotensin receptor blockade decreases markers of vascular inflammation.

A protective role against atherosclerosis can be attributed to angiotensin converting enzyme inhibitors (ACE-I), since they have been shown to reduce mortality in patients at cardiovascular risk. Since plasma levels of adhesion molecules are considered surrogate markers of endothelial cell activation and atherogenesis, we compared the levels of adhesion molecules after treatment with the ACE-I enalapril or the direct angiotensin- receptor antagonist losartan or placebo. In a randomized, controlled trial, 21 hypercholesterolemic volunteers received 50 mg/d losartan or 20 mg/d enalapril or placebo for twelve weeks. Plasma levels of circulating intercellular adhesion molecule-1 (cICAM-1), vascular adhesion molecule-1 (cVCAM-1), and E-selectin (cE-SEL) were measured by ELISA. Surface expression of ICAM-1 on circulating leukocytes was determined by flow cytometry. Enalapril and losartan but not placebo induced a small but stable decrease of cICAM-1 and cVCAM-1, while cE-SEL and leukocyte expression of ICAM-1 remained unchanged. The lowering of plasma adhesion molecules may indicate an antiatherogenic effect of angiotensin II blockade in hypercholesterolemia. While such preventive effect will have to be proven in clinical trials, our results do not support a preference for either enalapril or losartan with regard to their possible vasoprotective role.