OBJECTIVES: The study was done to determine the role of partial agonist activity in the lack of effectiveness of the oral GPIIb/IIIa antagonist orbofiban. BACKGROUND: Orbofiban, an oral GPIIb/IIIa antagonist, was found to increase the mortality of patients with acute coronary syndromes (ACS) in the OPUS-TIMI-16 trial, despite the fact that it is a very potent anti-platelet agent and that IV agents have proven very effective. METHODS:Patients (n = 520) with ACS were randomized to orbofiban 30 mg, 40 mg or 50 mg twice daily or 50 mg once daily or placebo. Platelet activity was assessed in 175 patients by examining GPIIb/IIIa receptor conformation, expression of CD63 antigen, and platelet aggregation. RESULTS:Plasma concentrations of orbofiban at the highest dose (74 +/- 6 ng/ml peak, 61 +/- 5 ng/ml trough) exceeded the IC50 for platelet aggregation to adenosine diphosphate (ADP) (29 +/- 6 ng/ml) and thrombin-activating peptide (61 +/- 18 ng/ml). Orbofiban induced a conformational change in GPIIb/IIIa detected as the displacement of the monoclonal antibody mAb2; such conformational changes have been linked to partial agonist activity. Consistent with this, platelet expression of CD63 ex vivo was significantly increased at five time points during the study. In vitro, orbofiban increased platelet aggregation to a submaximal concentration of epinephrine (67 +/- 19% vs. 27 +/- 9%, n = 5) and increased thromboxane formation when the platelet GPIIb/IIIa were clustered using monoclonal antibodies to the receptor. CONCLUSIONS: Orbofiban is both an antagonist and a partial agonist of platelet GPIIb/IIIa. At low concentrations of the drug, this partial agonist activity may enhance platelet aggregation. Along with suboptimal plasma drug levels, these findings may help explain the lack of efficacy seen with orbofiban in patients with ACS.
RCT Entities:
OBJECTIVES: The study was done to determine the role of partial agonist activity in the lack of effectiveness of the oral GPIIb/IIIa antagonist orbofiban. BACKGROUND:Orbofiban, an oral GPIIb/IIIa antagonist, was found to increase the mortality of patients with acute coronary syndromes (ACS) in the OPUS-TIMI-16 trial, despite the fact that it is a very potent anti-platelet agent and that IV agents have proven very effective. METHODS:Patients (n = 520) with ACS were randomized to orbofiban 30 mg, 40 mg or 50 mg twice daily or 50 mg once daily or placebo. Platelet activity was assessed in 175 patients by examining GPIIb/IIIa receptor conformation, expression of CD63 antigen, and platelet aggregation. RESULTS: Plasma concentrations of orbofiban at the highest dose (74 +/- 6 ng/ml peak, 61 +/- 5 ng/ml trough) exceeded the IC50 for platelet aggregation to adenosine diphosphate (ADP) (29 +/- 6 ng/ml) and thrombin-activating peptide (61 +/- 18 ng/ml). Orbofiban induced a conformational change in GPIIb/IIIa detected as the displacement of the monoclonal antibody mAb2; such conformational changes have been linked to partial agonist activity. Consistent with this, platelet expression of CD63 ex vivo was significantly increased at five time points during the study. In vitro, orbofiban increased platelet aggregation to a submaximal concentration of epinephrine (67 +/- 19% vs. 27 +/- 9%, n = 5) and increased thromboxane formation when the platelet GPIIb/IIIa were clustered using monoclonal antibodies to the receptor. CONCLUSIONS:Orbofiban is both an antagonist and a partial agonist of platelet GPIIb/IIIa. At low concentrations of the drug, this partial agonist activity may enhance platelet aggregation. Along with suboptimal plasma drug levels, these findings may help explain the lack of efficacy seen with orbofiban in patients with ACS.
Authors: Jihong Li; Yoshiyuki Fukase; Yi Shang; Wei Zou; José M Muñoz-Félix; Lorena Buitrago; Johannes van Agthoven; Yixiao Zhang; Ryoma Hara; Yuta Tanaka; Rei Okamoto; Takeshi Yasui; Takashi Nakahata; Toshihiro Imaeda; Kazuyoshi Aso; Yuchen Zhou; Charles Locuson; Dragana Nesic; Mark Duggan; Junichi Takagi; Roger D Vaughan; Thomas Walz; Kairbaan Hodivala-Dilke; Steven L Teitelbaum; M Amin Arnaout; Marta Filizola; Michael A Foley; Barry S Coller Journal: ACS Pharmacol Transl Sci Date: 2019-08-02