title: Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty.
abstract: BACKGROUND
  Thrombosis has been implicated as central to the clinical complications of coronary angioplasty (PTCA). Chimeric monoclonal 7E3 Fab (c7E3 Fab) is the first of a new class of antiplatelet drugs directed at the platelet glycoprotein IIb/IIIa integrin. This study was performed to determine the pharmacodynamics of c7E3 Fab administration during PTCA and to gain an initial clinical experience with this novel agent.
  
  
  RESULTS
  The study was a multicenter, open-label, dose-escalation study conducted in two stages. Enrollment included 56 patients scheduled for elective PTCA who were estimated to be at moderate to high risk of sustaining ischemic complications. All patients were given aspirin and heparin. The study drug was given at least 10 minutes before PTCA. In stage 1, increasing bolus doses of c7E3 Fab were given to 15 patients; a bolus dose of 0.25 mg/kg was found to result in blockade of > 80% of the receptors and reduce platelet aggregation to < 20% compared with baseline, establishing this dose as that necessary to sufficiently suppress platelet activity. In stage 2, additional c7E3 Fab was administered by continuous infusion to 32 patients for progressively longer periods of time (up to 24 hours) to confirm that platelet inhibition could be maintained with prolonged drug infusion. Also, 9 patients otherwise meeting entry criteria were given placebo. There were no thrombotic events among patients receiving c7E3 Fab. Overall procedural and clinical success and complication rates as well as rates of bleeding were statistically similar among groups. However, minor bleeding was more frequent with administration of the active drug.
  
  
  CONCLUSIONS
  The novel antiplatelet agent c7E3 Fab can be administered during PTCA in combination with aspirin and heparin. Suppression of platelet activity is dose dependent and can be maintained for up to 24 hours. Further evaluation will be required to determine the extent of improvement in ischemic complication and restenosis rates and to provide additional insight into the safety profile of this potent monoclonal platelet antibody.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors.forename: J E
authors.initials: JE
authors.lastname: Tcheng
authors.forename: S G
authors.initials: SG
authors.lastname: Ellis
authors.forename: B S
authors.initials: BS
authors.lastname: George
authors.forename: D J
authors.initials: DJ
authors.lastname: Kereiakes
authors.forename: N S
authors.initials: NS
authors.lastname: Kleiman
authors.forename: J D
authors.initials: JD
authors.lastname: Talley
authors.forename: A L
authors.initials: AL
authors.lastname: Wang
authors.forename: H F
authors.initials: HF
authors.lastname: Weisman
authors.forename: R M
authors.initials: RM
authors.lastname: Califf
authors.forename: E J
authors.initials: EJ
authors.lastname: Topol
mesh_terms: D000077284:Abciximab; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D007432:Intraoperative Period; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011300:Preoperative Care; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D000077284:Abciximab