A phase I trial of alfimeprase for peripheral arterial thrombolysis

Kenneth Ouriel, Jacob Cynamon, Fred A. Weaver, Herbert Dardik, Donald Akers, John Blebea, Laura Gruneiro, Christopher F. Toombs, Fong Wang-Clow, Margie Mohler, Luis Pena, Ching Yi Wan, Steven R. Deitcher

Research output: Contribution to journalArticle

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Abstract

PURPOSE: To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO). MATERIALS AND METHODS: In this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as α2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and α2-macroglobulin-bound (ie, total) alfimeprase. RESULTS: No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum α2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure. CONCLUSIONS: Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.

Original languageEnglish (US)
Pages (from-to)1075-1083
Number of pages9
JournalJournal of Vascular and Interventional Radiology
Volume16
Issue number8
DOIs
StatePublished - Aug 2005
Externally publishedYes

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Macroglobulins
Fibrinogen
Pharmacokinetics
Safety
Thrombosis
Hemorrhage
alfimeprase
Fibrinolytic Agents
Vital Signs
Plasminogen
Exanthema
Serum
Headache
Half-Life
Lower Extremity
Therapeutics
Ischemia
Antibodies
Incidence

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology

Cite this

A phase I trial of alfimeprase for peripheral arterial thrombolysis. / Ouriel, Kenneth; Cynamon, Jacob; Weaver, Fred A.; Dardik, Herbert; Akers, Donald; Blebea, John; Gruneiro, Laura; Toombs, Christopher F.; Wang-Clow, Fong; Mohler, Margie; Pena, Luis; Wan, Ching Yi; Deitcher, Steven R.

In: Journal of Vascular and Interventional Radiology, Vol. 16, No. 8, 08.2005, p. 1075-1083.

Research output: Contribution to journalArticle

Ouriel, K, Cynamon, J, Weaver, FA, Dardik, H, Akers, D, Blebea, J, Gruneiro, L, Toombs, CF, Wang-Clow, F, Mohler, M, Pena, L, Wan, CY & Deitcher, SR 2005, 'A phase I trial of alfimeprase for peripheral arterial thrombolysis', Journal of Vascular and Interventional Radiology, vol. 16, no. 8, pp. 1075-1083. https://doi.org/10.1097/01.RVI.0000167863.10122.2A
Ouriel, Kenneth ; Cynamon, Jacob ; Weaver, Fred A. ; Dardik, Herbert ; Akers, Donald ; Blebea, John ; Gruneiro, Laura ; Toombs, Christopher F. ; Wang-Clow, Fong ; Mohler, Margie ; Pena, Luis ; Wan, Ching Yi ; Deitcher, Steven R. / A phase I trial of alfimeprase for peripheral arterial thrombolysis. In: Journal of Vascular and Interventional Radiology. 2005 ; Vol. 16, No. 8. pp. 1075-1083.
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AU - Ouriel, Kenneth

AU - Cynamon, Jacob

AU - Weaver, Fred A.

AU - Dardik, Herbert

AU - Akers, Donald

AU - Blebea, John

AU - Gruneiro, Laura

AU - Toombs, Christopher F.

AU - Wang-Clow, Fong

AU - Mohler, Margie

AU - Pena, Luis

AU - Wan, Ching Yi

AU - Deitcher, Steven R.

PY - 2005/8

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N2 - PURPOSE: To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO). MATERIALS AND METHODS: In this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as α2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and α2-macroglobulin-bound (ie, total) alfimeprase. RESULTS: No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum α2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure. CONCLUSIONS: Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.

AB - PURPOSE: To evaluate the safety profile, pharmacokinetics, and thrombolytic activity of alfimeprase, a novel direct-acting thrombolytic agent, in patients with chronic peripheral arterial occlusion (PAO). MATERIALS AND METHODS: In this multicenter, open-label, single-dose, dose-escalation study, 20 patients with worsening symptoms of lower extremity ischemia within 6 months of enrollment were treated with alfimeprase in five escalating dose cohorts (0.025 mg/kg, 0.05 mg/kg, 0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) by means of intraarterial and sometimes intrathrombic pulsed infusion. The primary endpoint was safety assessed by adverse event rates. Additional safety assessments included vital sign monitoring, serum chemistry testing, hematologic testing, and coagulation testing for 28 days after the procedure, as well as α2-macroglobulin and antialfimeprase antibody testing for as long as 3 months after treatment. Pharmacokinetic parameters were evaluated with use of an assay that measures free and α2-macroglobulin-bound (ie, total) alfimeprase. RESULTS: No patient experienced a hemorrhagic adverse event. Mean plasminogen and fibrinogen concentrations were not substantially altered by treatment. Three transient treatment-related adverse events were reported in the same patient: one incidence each of increased blood fibrinogen level, skin rash, and headache. All three adverse events were graded as mild. The pharmacokinetic profile of alfimeprase suggested that the half-life for total alfimeprase ranges from 11 to 54 minutes (median, 25 min) in patients with PAO. The serum α2-macroglobulin concentrations decreased transiently in a dose response-like manner between 12 and 24 hours and returned to within normal limits approximately 14 days after alfimeprase exposure. CONCLUSIONS: Alfimeprase in doses as high as 0.5 mg/kg was generally well-tolerated in patients with chronic PAO. No bleeding complications were noted. The stable fibrinogen concentrations suggest that the activity of alfimeprase may be limited to the target thrombus. Alfimeprase holds the potential to achieve dissolution of thrombus with a diminished risk of hemorrhage.

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