- Email: [email protected]
Studies in human pharmacology of recombinant hirudin
ABSTRACTS OF 12TH INTNAT’L CONGRESS
S118
Vol. 65, Suppl. 1
C231 STUDIES 1N HUMAN PHARMACOLOGY OF RECOMBINANT HIRUDIN E. Glusa’, J. Schenkl, K. Breddinz, A. Butti’ and F. Markwardt’ Llnstitute of Pharmacology and Toxicology, Medical Academy Erfurt, Erfurt, D’ Division of Angiology, Department of Internal Medicine, J.W. Goethe University, Frankfurt, D’ IKETON Farmaceutici s.r.l., Segrate (Milano), 1 Pharmacological profiling of recombinant hirudin has shown that this selective tight-binding thrombin inhibitor is a potent, well-tolerated anticoagulant (E Markwardt et al., Pharmazie 43,202, 1988; Tbromb. Res. 52,393, 1988). To prepare the clinical use of the inhibitor its tolerance and pharmacokinetic behavior in man were-studied. Recombinant hirudin (rH) was obtained by a recombinant production Technology by which the protein is secreted in the fermentation broth, instead of being included in the body of E. Coli (IKETON Pharmaceutici). Volunteers were treated with single i.v. dose of rH in the range of 0.1-0.3 n&kg; intravenous continuous infusion of 0.03 mg/kgihr for 4 hrs; single subcutaneous injection in the range of 0.1-0.5 mg& or with repeated subcutaneous injection of 0.3 mg/kg twice a day for 5 days. Administration of rH was tolerated without perceptible side effects or allergic reactions. No changes in blood pressure, heart or respiratory rates were observed. For pharmacokinetic studies an assay was used which detects rH by its antithrombin activity. Absorption, distribution and elimination of rH corresponded to the results obtained with native hirudin. The effects on the haemostatic system were evaluated. Thrombin time and partial thromboplastin time were prolonged dependent on the rH-level in plasma. Clinical chemistry tests and haematologicai values remained uneffected. The results corroborated the pharmacological properties of rH previously found in animal experiments. Thus, rH proved
to be a potent
antithrombotic
agent.
C232 TREATMENT OF SEVERE PILOT STUDY
VENOUS
THROMBO-EMBOLISM
E Parent, F. Bridey, M. Dre$us, D. Mussel, G. Grimon, HGpital A. B&l&e, Universite Paris-Sud, Clamart, F
WITH
INTRAVENOUS
HIRUDIN
(HBW
023): AN OPEN
D. Meyer, G. Simonneau
Recombinant hirudin (rH) is a new drug with specific antithrombin activity independent of antithmmbin III or heparin cofactor II. From the data available in various in vitro models and animal studies, it can be expected that rH will be more effective than heparin, however no data on the treatment of human venous thmmbo-embolism (VTE) are presently available. We report the results of the first open pilot study on the curative treatment of acute VTE with rH (HBW 023) in 10 patients (pts). The aim of the study was to collect preliminary information concerning safety and efficacy of HBW 023 prior to a phase II dose-ranging study. The lirst dose of HBW 023 tested was 0.07 mg/kg (iv bolus) followed by 0.05 mg/kg/h (iv infusion) for 5 f I days, without APT’l’ adjustment. During the study, it was planned to modify the dosage ofrH in case of recurrence ofV’fE or major bleeding. Written informed consent was obtained. After completion of the study, anticoagulation with rH was switched 10 an association of heparin and acenocoumarol during at least 5 days, followed by acenocoumarol alone for at kast three months, The 10 pts had a proximal deep vein thrombosis (DVT) conlirmed by venography, associated with a non life-threatening pulmonary embolism (PE) confirmed in all but one patients by pulmonary angiography. At inclusion, the upper limit of the clot was vena caval in 1 pt, iliac in 2, femoral in 4, popliteal in 3; the angiographic pulmonary vascular obstruction (PVO) was47 i 17% (assessed by Miller index). Efficacy was consistently assessed by venography and perfusion lung scan on day 1 and day 5. Within the 5 days of trial, we did not observe any death, or major bleeding, or clinical suspicion of DVT extension or PE recurrence; no premature cessation of treatment was required. APTT ranged from I .4 lo 2.8 the control. On the second perftion lung scan at day 5, no nnv defect was observed except in 1 pt, for whom PE recurrence was eliminated by pulmonary angiography. Between day I and day 5, the perfusion lung scan PVO improved from 44 f 9% to 37 i 10% (p < 0.05); the venographic upper limit of the clot was unchanged in 7 pts, improved in 2 and worsened in I; the Marder score was not significantly modified. No complication occured during the following three months. Conclusion. The dosage of hirudin assessed in this study (HBW 023: 0.07 mg/kg iv bolus followed by 0.05 m%kg/h iv infusion) seems 10 be safe and efficient and could be used as the initial dose of the further phase II dose-ranging study: the observed efficacy is strengthened by the severity of VTE in our patients. These conclusions have lo be taken with caution however, because of the small group of patients and the short duration of the trial.
S118
Vol. 65, Suppl. 1
C231 STUDIES 1N HUMAN PHARMACOLOGY OF RECOMBINANT HIRUDIN E. Glusa’, J. Schenkl, K. Breddinz, A. Butti’ and F. Markwardt’ Llnstitute of Pharmacology and Toxicology, Medical Academy Erfurt, Erfurt, D’ Division of Angiology, Department of Internal Medicine, J.W. Goethe University, Frankfurt, D’ IKETON Farmaceutici s.r.l., Segrate (Milano), 1 Pharmacological profiling of recombinant hirudin has shown that this selective tight-binding thrombin inhibitor is a potent, well-tolerated anticoagulant (E Markwardt et al., Pharmazie 43,202, 1988; Tbromb. Res. 52,393, 1988). To prepare the clinical use of the inhibitor its tolerance and pharmacokinetic behavior in man were-studied. Recombinant hirudin (rH) was obtained by a recombinant production Technology by which the protein is secreted in the fermentation broth, instead of being included in the body of E. Coli (IKETON Pharmaceutici). Volunteers were treated with single i.v. dose of rH in the range of 0.1-0.3 n&kg; intravenous continuous infusion of 0.03 mg/kgihr for 4 hrs; single subcutaneous injection in the range of 0.1-0.5 mg& or with repeated subcutaneous injection of 0.3 mg/kg twice a day for 5 days. Administration of rH was tolerated without perceptible side effects or allergic reactions. No changes in blood pressure, heart or respiratory rates were observed. For pharmacokinetic studies an assay was used which detects rH by its antithrombin activity. Absorption, distribution and elimination of rH corresponded to the results obtained with native hirudin. The effects on the haemostatic system were evaluated. Thrombin time and partial thromboplastin time were prolonged dependent on the rH-level in plasma. Clinical chemistry tests and haematologicai values remained uneffected. The results corroborated the pharmacological properties of rH previously found in animal experiments. Thus, rH proved
to be a potent
antithrombotic
agent.
C232 TREATMENT OF SEVERE PILOT STUDY
VENOUS
THROMBO-EMBOLISM
E Parent, F. Bridey, M. Dre$us, D. Mussel, G. Grimon, HGpital A. B&l&e, Universite Paris-Sud, Clamart, F
WITH
INTRAVENOUS
HIRUDIN
(HBW
023): AN OPEN
D. Meyer, G. Simonneau
Recombinant hirudin (rH) is a new drug with specific antithrombin activity independent of antithmmbin III or heparin cofactor II. From the data available in various in vitro models and animal studies, it can be expected that rH will be more effective than heparin, however no data on the treatment of human venous thmmbo-embolism (VTE) are presently available. We report the results of the first open pilot study on the curative treatment of acute VTE with rH (HBW 023) in 10 patients (pts). The aim of the study was to collect preliminary information concerning safety and efficacy of HBW 023 prior to a phase II dose-ranging study. The lirst dose of HBW 023 tested was 0.07 mg/kg (iv bolus) followed by 0.05 mg/kg/h (iv infusion) for 5 f I days, without APT’l’ adjustment. During the study, it was planned to modify the dosage ofrH in case of recurrence ofV’fE or major bleeding. Written informed consent was obtained. After completion of the study, anticoagulation with rH was switched 10 an association of heparin and acenocoumarol during at least 5 days, followed by acenocoumarol alone for at kast three months, The 10 pts had a proximal deep vein thrombosis (DVT) conlirmed by venography, associated with a non life-threatening pulmonary embolism (PE) confirmed in all but one patients by pulmonary angiography. At inclusion, the upper limit of the clot was vena caval in 1 pt, iliac in 2, femoral in 4, popliteal in 3; the angiographic pulmonary vascular obstruction (PVO) was47 i 17% (assessed by Miller index). Efficacy was consistently assessed by venography and perfusion lung scan on day 1 and day 5. Within the 5 days of trial, we did not observe any death, or major bleeding, or clinical suspicion of DVT extension or PE recurrence; no premature cessation of treatment was required. APTT ranged from I .4 lo 2.8 the control. On the second perftion lung scan at day 5, no nnv defect was observed except in 1 pt, for whom PE recurrence was eliminated by pulmonary angiography. Between day I and day 5, the perfusion lung scan PVO improved from 44 f 9% to 37 i 10% (p < 0.05); the venographic upper limit of the clot was unchanged in 7 pts, improved in 2 and worsened in I; the Marder score was not significantly modified. No complication occured during the following three months. Conclusion. The dosage of hirudin assessed in this study (HBW 023: 0.07 mg/kg iv bolus followed by 0.05 m%kg/h iv infusion) seems 10 be safe and efficient and could be used as the initial dose of the further phase II dose-ranging study: the observed efficacy is strengthened by the severity of VTE in our patients. These conclusions have lo be taken with caution however, because of the small group of patients and the short duration of the trial.