Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb/IIIa.
Most clinical trials with fibrinogen receptor antagonists (FRAs) have been associated with thrombocytopenia. This report describes the occurrence of thrombocytopenia in one chimpanzee and one rhesus monkey upon administration of potent FRAs. Chimpanzee A-264 experienced profound thrombocytopenia on two occasions immediately upon intravenous administration of two different potent FRAs, L-738, 167 and L-739,758. However, an equally efficacious antiaggregatory dose of another potent antagonist, L-734,217, caused no change in platelet count. These compounds did not affect platelet count in five other chimpanzees or numerous other nonhuman primates. Flow cytometric analysis showed drug-dependent antibodies (DDAbs) in the plasma of chimpanzee A-264 that bound to platelets of chimpanzees, humans, and all other primates tested only in the presence of the compounds that induced thrombocytopenia. Rhesus monkey 94-R021 experienced thrombocytopenia upon administration of a different antagonist, L-767,679, and several prodrugs that are converted into the active form, L-767,679, in the blood. More than 20 other FRAs, including those that induced thrombocytopenia in chimpanzee A-264, had no effect on platelet count in this monkey. Flow cytometric measurements again identified DDAbs that reacted with platelets of all primates tested and required the presence of L-767,679. Screening for DDAbs in the plasma of 1,032 human subjects with L-738, 167 and L-739,758 demonstrated that the incidence of these preexisting antibodies in this population was 0.8% +/- 0.6% and 1.1% +/- 0.6%, respectively.
Bednar
B
B
Departments of Pharmacology and Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA. bohumil_bednar@merck.com
Cook
J J
JJ
Holahan
M A
MA
Cunningham
M E
ME
Jumes
P A
PA
Bednar
R A
RA
Hartman
G D
GD
Gould
R J
RJ
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology; D001381:Azepines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D001792:Blood Platelets / Q000276:immunology; D004198:Disease Susceptibility; D004285:Dogs; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008253:Macaca mulatta / Q000097:blood* / Q000276:immunology; D046911:Macromolecular Substances; D008297:Male; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry; D002679:Pan troglodytes / Q000097:blood* / Q000276:immunology; D010879:Piperazines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D010880:Piperidines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000276:immunology*; D011323:Primates; D011485:Protein Binding; D013449:Sulfonamides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000276:immunology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity
D001323:Autoantibodies; D001381:Azepines; D000939:Epitopes; D005343:Fibrinolytic Agents; D007074:Immunoglobulin G; C105929:L 738167; C120272:L 739758; C108346:L 767679; D046911:Macromolecular Substances; D009842:Oligopeptides; D010879:Piperazines; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D015091:beta-Alanine; C095356:L 734217; C047981:arginyl-glycyl-aspartic acid