Mechanistic Modeling of the Pharmacodynamic and Pharmacokinetic Relationship of Tissue Factor Pathway Inhibitor-Neutralizing Antibody (BAY 1093884) in Cynomolgus Monkeys

The AAPS Journal
Jian-Ming GuMaria Koellnberger

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 re...Continue Reading

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Citations

Oct 12, 2017·Blood·Valder R ArrudaBenjamin J Samelson-Jones
Jun 12, 2018·Expert Review of Hematology·Giancarlo Castaman, Silvia Linari
Oct 2, 2019·Journal of Thrombosis and Haemostasis : JTH·Josefin Ahnström
May 1, 2019·Expert Opinion on Biological Therapy·Giancarlo Castaman, Silvia Linari
Jan 7, 2020·Médecine sciences : M/S·Yves GruelPeter Lenting
May 30, 2020·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Rudolf HartmannMichael Dockal
May 18, 2018·F1000Research·Valder R ArrudaBenjamin J Samelson-Jones
Feb 6, 2020·Expert Opinion on Investigational Drugs·Massimo FranchiniGiancarlo Maria Liumbruno
Dec 10, 2019·International Journal of Hematology·Midori Shima
Sep 14, 2019·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Saturnino Haya
Feb 2, 2018·Therapeutic Advances in Hematology·Pauline Balkaransingh, Guy Young
Feb 13, 2021·Pediatric Blood & Cancer·Yakun ZhaoJordan A Shavit
Dec 15, 2020·Research and Practice in Thrombosis and Haemostasis·Heechun KwakSung Ho Hwang
Mar 21, 2021·Haemophilia : the Official Journal of the World Federation of Hemophilia·Victor Jiménez-YusteSilva Zupančić Šalek
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Apr 30, 2021·Haemophilia : the Official Journal of the World Federation of Hemophilia·Erika J MartinDonald F Brophy

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Methods Mentioned

BETA
enzyme-linked immunosorbent assay
ELISA
Assay

Software Mentioned

Biacore
Phoenix
ToxKin

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