Pharmacokinetics and pharmacodynamics of AJW200, a humanized monoclonal antibody to von Willebrand factor, in monkeys.
The interaction between platelet glycoprotein Ib and von Willebrand factor (vWF) plays a crucial role in platelet-mediated thrombus formation under high-shear-stress conditions. The aim of this study was to investigate the antiplatelet profile of a humanized anti-vWF monoclonal antibody, AJW200. In vitro studies were performed with a modified cone-and-plate viscometer and human platelets. AJW200 inhibited high-shear-stress-induced platelet adhesion, aggregation, and thrombin generation, but it did not have such effects under low-shear-stress conditions. Although abciximab inhibited platelet aggregation under both shear stress conditions, it did not inhibit platelet adhesion and thrombin generation. In addition, the pharmacokinetics and pharmacodynamics of AJW200 were evaluated in cynomolgus monkeys. Sustained inhibition of ristocetin-induced platelet aggregation was observed over 24 hours, 6 days, and 2 weeks after a single bolus injection of 0.3, 1, and 3 mg/kg, respectively. Moderate prolongation of the bleeding time was observed at the doses of 1 and 3 mg/kg. Abciximab markedly prolonged the bleeding time at 0.4 mg/kg, at which concentration complete inhibition of ADP-induced platelet aggregation was observed. These results suggest that glycoprotein Ib-vWF blockade with AJW200 results in a sustained antiplatelet effect without extensive prolongation of the bleeding time, probably due to a shear-stress-dependent inhibitory action.
Kageyama
Shunsuke
S
Developmental Research Laboratories, Pharmaceutical Research Laboratories, Ajinomoto Co, Inc, Kanagawa, Japan.
Yamamoto
Hiroshi
H
Nakazawa
Harumi
H
Matsushita
Junko
J
Kouyama
Tetsuya
T
Gonsho
Akinori
A
Ikeda
Yasuo
Y
Yoshimoto
Ryota
R
D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D018056:Hemorheology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D008252:Macaca fascicularis; D010973:Platelet Adhesiveness / Q000187:drug effects* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors / Q000276:immunology*; D012310:Ristocetin / Q000494:pharmacology; D013917:Thrombin / Q000096:biosynthesis*; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors / Q000276:immunology*
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D012310:Ristocetin; D013917:Thrombin; D000077284:Abciximab