Paul Tanswell

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 V1 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 V1. Total bodyweight explained 19% of the variability in CL and 11% of the variability in V1, 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 AUC2–90 exceeded 320 μg · min/ml, corresponding to an average plasma concentration of 3.6 μg/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.

Population Pharmacokinetics of Sibrotuzumab, A Novel Therapeutic Monoclonal Antibody, in Cancer Patients

Population pharmacokinetics of sibrotuzumab, a humanized monoclonal antibody directed against fibroblast activation protein, were determined after multiple intravenous infusions of dosages ranging from 5mg/m2 to an absolute dose of 100mg, in patients with advanced or metastatic carcinoma. In total, 1844 serum concentrations from 60 patients in three Phase I and II clinical studies were analyzed. The structural model incorporated two disposition compartments and two parallel elimination pathways from the central compartment, one linear and one nonlinear. Finally estimated pharmacokinetic parameters (%RSE) were: linear clearance CLL 22.1ml/h (9.6), central distribution volume V1 4.13l (3.7), peripheral volume V2 3.19l (8.8), inter-compartmental clearance Q 37.6ml/h (9.6); for the nonlinear clearance Vmax was 0.0338mg/h (25) and Km 0.219μg/ml (57). At serum concentrations between approximately 20ng/ml and 7μg/ml, the effect of the nonlinear clearance on pharmacokinetics was marked. Only at >7μg/ml did CLL dominate overall clearance. Interindividual variability was 57% for CLL, 20% for V1 and V2, and 29% for Vmax and was larger than the inter-occasional variability of 13%. Of the many investigated patient covariates, only body weight was found to contribute to the population model. It significantly affected CLL, V1, V2 and Vmax resulting in marked differences in the model-predicted concentration–time profiles after multiple dosing in patients with low and high body weights. In conclusion, a robust population pharmacokinetic model was developed and evaluated for sibrotuzumab, which identified a possible need to consider body weight when designing dosage regimen for future clinical cancer trials.

Pharmacokinetics and Pharmacodynamics of Tenecteplase: Results from a Phase II Study in Patients with Acute Myocardial Infarction

Tenecteplase is a site‐specific engineered tissue plasminogen activator (t‐PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose‐ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t‐PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt‐PA as the accelerated 90‐minute infusion regimen in this randomized, open‐label study. Tenecteplase and r‐tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half‐life of 22 minutes and a mean terminal half‐life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt‐PA has a fourfold faster plasma clearance. Pharmacokinetic‐pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r‐tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt‐PA, allowing dosing as an W bolus injection. Weight‐adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.

Sixty-minute alteplase protocol: a new accelerated recombinant tissue-type plasminogen activator regimen for thrombolysis in acute myocardial infarction.

OBJECTIVES Our aim was to design and evaluate a new and easily administered recombinant tissue-type plasminogen activator (rt-PA) regimen for thrombolysis in acute myocardial infarction (AMI) based on established pharmacokinetic data that improve the reperfusion success rate. BACKGROUND Rapid restoration of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow is a primary predictor of mortality after thrombolysis in AMI. However, TIMI grade 3 patency rates 90 min into thrombolysis of only 50% to 60% indicate an obvious need for improved thrombolytic regimens. METHODS Pharmacokinetic simulations were performed to design a new rt-PA regimen. We aimed for a plateau tissue-type plasminogen activator (t-PA) plasma level similar to that of the first plateau of the Neuhaus regimen. These aims were achieved with a 20-mg rt-PA intravenous (i.v.) bolus followed by an 80-mg i.v. infusion over 60 min (regimen A). This regimen was tested in a consecutive comparative trial in 80 patients versus 2.25 10(6) IU of streptokinase/60 min (B), and 70 mg (C) or 100 mg (D) of rt-PA over 90 min. Subsequently, a confirmation trial of regimen A in 254 consecutive patients was performed with angiographic assessment by independent investigators of patency at 90 min. RESULTS The comparative phase of the trial yielded, respectively, TIMI grade 3 and total patency (TIMI grades 2 and 3) of 80% and 85% (regimen A), 35% and 50% (B), 50% and 55% (C) and 60% and 70% (D). In the confirmation phase of the trial, regimen A yielded 81.1% TIMI grade 3 and 87.0% total patency. At follow-up angiography 7 (4.1%) of 169 vessels had reoccluded. In-hospital mortality rate was 1.2%. Nadir levels of fibrinogen, plasminogen and alpha2-antiplasmin were 3.6 +/- 0.8 mg/ml, 60 +/- 21% and 42 +/- 16%, respectively (mean +/- SD). Fifty-seven patients (22.4%) suffered from bleeding; 3.5% needed blood transfusions. CONCLUSIONS The 60-min alteplase thrombolysis in AMI protocol achieved a TIMI grade 3 patency rate of 81.1% at 90 min with no indication of an increased bleeding hazard; it was associated with a 1.2% overall mortality rate. These results are substantially better than those reported from all currently utilized regimens. Head to head comparison with established thrombolytic regimens in a large-scale randomized trial is warranted.