Bioequivalence of Intravenous Alteplase from Two Different Manufacturing Processes in Healthy Male Volunteers: Results from a Two-Stage, Adaptive-Design Study.

OBJECTIVE: Alteplase is a recombinant tissue plasminogen activator used for thrombolytic treatment in several indications and is currently approved in Europe under the brand name Actilyse®. The current manufacturing process for alteplase was recently modified to meet increasing global demands. The aim of this randomized, open-label, adaptive two-stage design, two-way crossover study was to establish bioequivalence of alteplase derived from the two manufacturing processes (modified versus current). METHODS: The two alteplase formulations (modified and current, 0.2 mg/kg body weight) were compared in healthy male volunteers after intravenous infusion over a period of 30 min. The trial was put on hold after treatment of 12 subjects (Part A) and restarted as Part B (n = 18) with design adaptations, including a heparin bolus. RESULTS: Pharmacokinetic parameters of alteplase were determined from plasma concentration-time profiles. The pharmacokinetic parameters tested (AUC0-tz, Cmax, and AUC0-∞) for alteplase after single intravenous infusion demonstrated no differences between alteplase obtained from the modified and current processes. An analysis of variance (ANOVA) model was applied to test for bioequivalence. The geometric means ratio and the respective 92.83% confidence intervals (CIs) for all primary and secondary pharmacokinetic endpoints were well within the prespecified equivalence boundaries of 80-125%. The CIs also included unity, suggesting no statistically significant differences between the two treatments. CONCLUSIONS: The results show that alteplase exposure was virtually identical for the formulations tested, and statistical evaluation demonstrated bioequivalence of the formulations. Both formulations of alteplase were well tolerated by the subjects at the single intravenous doses in the trial. TRIAL REGISTRATION: Trial registration number: NCT04419493, 2019-004932-40 (EudraCT Number).