Pharmacodynamics of abciximab during angioplasty: comparison to healthy subjects.
OBJECTIVE
Our objectives were to compare and contrast abciximab concentration-effect relationships in healthy volunteer participants with those in patients with coronary atherosclerosis undergoing elective coronary angioplasty. We also aimed to establish abciximab plasma concentrations associated with 80% inhibition of platelet aggregation.


METHODS
Abciximab clearance and concentration-effect relationships were determined from two separate clinical studies, one in 30 healthy subjects aged 21 to 66 years and the other in 32 patients aged 44 to 74 years before they underwent elective coronary angioplasty. After abciximab administration, abciximab plasma concentrations, platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor occupancy, and degree of inhibition of platelet aggregation in the presence of 5-micromol/L and 20-micromol/L adenosine diphosphate was determined. With an E(max) (receptor occupancy) or inhibitory E(max) (inhibition of platelet aggregation) model, abciximab concentrations required for 80% receptor occupancy and 80% inhibition of platelet aggregation were determined.


RESULTS
Abciximab steady-state clearance in healthy participants was 183 +/- 72 ml/min (mean +/- SD), and single-dose clearance in patients undergoing angioplasty was 405 +/- 240 ml/min (mean +/- SD). Abciximab concentration required for 80% GP IIb/IIIa receptor occupancy was 35.2 +/- 2.4 versus 72.8 +/- 6.4 ng/ml in healthy participants versus patients (P <.01). Concentrations required for 80% inhibition of platelet aggregation stimulated by 5-micromol/L adenosine diphosphate were 25.6 +/- 1.6 versus 68.9 +/- 9.2 ng/ml (P <.01). Similarly, the concentrations required for 80% inhibition of platelet aggregation stimulated by 20-micromol/L adenosine diphosphate were 56.0 +/- 3.2 versus 141 +/- 16.8 ng/ml (P <.01).


CONCLUSIONS
Approximately 2-fold greater abciximab exposure is required to achieve the same degree of GP IIb/IIIa occupancy and inhibition of platelet aggregation in patients undergoing angioplasty as compared with healthy participants. The difference between groups may be related either to different states of basal platelet activation or to the effect of heparin that patients received as part of the angioplasty procedure. A therapeutic concentration range for patients is 100 to 175 ng/ml, because this is the concentration consistent with >80% inhibition of platelet aggregation when 20-micromol/L adenosine diphosphate is used as the aggregating stimulus.
Abernethy
Darrell R
DR
Division of Clinical Pharmacology, Georgetown University School of Medicine, Washington, DC, USA. abernethyd@grc.nia.nih.gov
Pezzullo
John
J
Mascelli
Mary A
MA
Frederick
Bart
B
Kleiman
Neal S
NS
Freedman
Jane
J
D000077284:Abciximab; D000328:Adult; D000368:Aged; D017130:Angioplasty; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000601:surgery; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000187:drug effects*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000077284:Abciximab