A phase I trial of alfimeprase for peripheral arterial thrombolysis.
OBJECTIVE
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).


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 alpha2-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 alpha2-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 alpha2-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.
Ouriel
Kenneth
K
Department of Vascular Surgery, Desk S40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. ourielk@ccf.org
Cynamon
Jacob
J
Weaver
Fred A
FA
Dardik
Herbert
H
Akers
Donald
D
Blebea
John
J
Gruneiro
Laura
L
Toombs
Christopher F
CF
Wang-Clow
Fong
F
Mohler
Margie
M
Pena
Luis
L
Wan
Ching-Yi
CY
Deitcher
Steven R
SR
D000328:Adult; D000368:Aged; D000792:Angiography; D001779:Blood Coagulation Factors / Q000032:analysis; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006400:Hematocrit; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007866:Leg / Q000098:blood supply*; D008297:Male; D008666:Metalloendopeptidases / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D015912:Thrombolytic Therapy; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*; D000511:alpha-Macroglobulins / Q000032:analysis
D001779:Blood Coagulation Factors; D005343:Fibrinolytic Agents; D006454:Hemoglobins; D000511:alpha-Macroglobulins; D008666:Metalloendopeptidases; C436755:alfimeprase