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1.
AAPS J ; 19(4): 1186-1195, 2017 07.
Article in English | MEDLINE | ID: mdl-28516358

ABSTRACT

BAY 1093884 is a fully human monoclonal antibody against the tissue factor pathway inhibitor (TFPI) in development as prophylaxis in patients with hemophilia with or without inhibitors. In vitro, BAY 1093884 binds to human, mouse, and monkey TFPI. The objective of this study was to find a pharmacodynamic (PD) biomarker after administration of BAY 1093884 to normal monkeys. In monkey plasma, BAY 1093884 exhibited an IC50 (concentration that inhibits 50%) of 4.65 and 6.19 nM for free TFPI and diluted prothrombin time (dPT), respectively. The BAY 1093884 pharmacokinetic (PK) profile and its PD effects on dPT and free TFPI levels were assessed after intravenous and subcutaneous administration of BAY 1093884 (5 and 20 mg/kg) to female cynomolgus monkeys. Free TFPI concentrations in plasma decreased rapidly and increased to baseline in a dose-dependent manner. dPT clotting time was shortened and correlated with free TFPI levels and drug concentration in plasma, demonstrating the relationship between PD activities (dPT clotting time and free TFPI levels) and drug concentration. BAY 1093884 exhibited nonlinear PK, and a target-mediated drug disposition model was used to characterize the BAY 1093884 versus TFPI concentration-response relationship. We concluded that a mechanism-based PK/PD binding model could be useful for predicting human response to BAY 1093884. For the first-in-human study, measurement of free TFPI will be included as part of the dose-escalation design.


Subject(s)
Antibodies, Neutralizing/pharmacology , Lipoproteins/immunology , Animals , Antibodies, Neutralizing/immunology , Enzyme-Linked Immunosorbent Assay , Female , Macaca fascicularis
2.
Thromb Haemost ; 99(1): 190-5, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18217153

ABSTRACT

Acetylsalicylic acid (ASA) and the thienopyridine clopidogrel are established anti-platelet drugs that significantly reduce secondary cardiovascular events in patients with manifest atherosclerosis. However, their impact on atherosclerotic lesion development remains controversial. Four-week-old ApoE-deficient mice were randomly assigned to four groups receiving a cholesterol diet together with either ASA (5 mg/kg), or clopidogrel (25 mg/kg), or a combination of both ASA and clopidogrel, or vehicle for 8-12 weeks. Using intravital microscopy we found that daily administration of ASA in combination with clopidogrel reduces platelet thrombus formation following rupture of atherosclerotic plaque in vivo by approximately 50%. However, therapy with ASA or clopidogrel alone, or in combination for a period of 8-12 weeks had no significant effect on adhesion of platelets to dysfunctional endothelial cells or on atherosclerotic lesion formation in the aortic root or the carotid artery. In conclusion, anti-platelet therapy is effective in reducing platelet adhesion and subsequent thrombus formation following rupture of atherosclerotic plaque in vivo. However, our data do not support a role of either drug in the primary prevention of atherosclerosis in ApoE-deficient mice.


Subject(s)
Apolipoproteins E/metabolism , Aspirin/pharmacology , Atherosclerosis/prevention & control , Blood Platelets/drug effects , Platelet Aggregation Inhibitors/pharmacology , Thrombosis/prevention & control , Ticlopidine/analogs & derivatives , Animals , Aorta/drug effects , Aorta/metabolism , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Aspirin/administration & dosage , Atherosclerosis/blood , Atherosclerosis/complications , Atherosclerosis/etiology , Atherosclerosis/pathology , Blood Platelets/metabolism , Carotid Arteries/drug effects , Carotid Arteries/metabolism , Cholesterol, Dietary , Clopidogrel , Disease Models, Animal , Disease Progression , Drug Administration Schedule , Drug Therapy, Combination , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Microscopy, Video , Platelet Adhesiveness/drug effects , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Rupture , Thrombosis/blood , Thrombosis/etiology , Thrombosis/pathology , Ticlopidine/administration & dosage , Ticlopidine/pharmacology , Time Factors
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