Comparison of Dose Regimens for the Administration of Recombinant Pro-urokinase in a Canine Thrombosis Model

Abstract

Pro-urokinase represents an important addition to the array of thrombolytic drugs currently available for clinical use because of its high clot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precursor of high molecular weight urokinase which has been expressed in a mouse myeloma cell line. The present study was conducted to determine the dosing regimen which would produce optimal clot lysis and restoration of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radio-labelled clot which was formed in the heat-damaged femoral arteries of 39 male beagle dogs. The animals were divided into six heparinized treatment groups, each receiving one of five dosing regimens or the vehicle for r-proUK. The total dose (80,000 U/kg) was divided into an initial loading bolus, followed by either a second bolus or by infusions for various time periods, as shown below: Group Treatment Regimen % Lysis 1 r-proUK Bolus/bolus, 50%/50% at 0 and 15 min 52 +/- 7 2 r-proUK Bolus/bolus, 50%/50% at 0 and 30 min 62 +/- 7 3 r-proUK Bolus/infusion, 20%/80% infused to 30 min 41 +/- 8 4 r-proUK Bolus/infusion, 20%/80% infused to 60 min 66 +/- 5 5 r-proUK Bolus/infusion, 50%/50% infused to 30 min 73 +/- 4 6 Vehicle Bolus/infusion, 50%/50% infused to 30 min 12 +/- 6 It was concluded that optimal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed immediately by the remaining 50% given as a 30 min intravenous infusion (Group 5). At the dose used in this study, r-proUK did not produce degradation of fibrinolytic or hemostatic plasma proteins.