A Systems Pharmacology Model for Predicting Effects of Factor Xa Inhibitors in Healthy Subjects: Assessment of Pharmacokinetics and Binding Kinetics

CPT: Pharmacometrics & Systems Pharmacology
X ZhouRahj Gilissen

Abstract

Factor Xa (FXa) emerged as a promising target for effective anticoagulation and several FXa inhibitors are now available for the prevention of venous thromboembolism. However, in previously reported pharmacokinetic/pharmacodynamic (PK/PD) models, the complex coagulation processes and detailed information of drug action are usually unclear, which makes it difficult to predict clinical outcome at the drug discovery stage. In this study, a large-scale systems pharmacology model was developed based on several published models and clinical data. It takes into account all pathways of the coagulation network, and captures drug-specific features: plasma pharmacokinetics and drug-target binding kinetics (BKs). We aimed to predict the anticoagulation effects of FXa inhibitors in healthy subjects, and to use this model to compare the effects of compounds with different binding properties. Our model predicts the clotting time and anti-FXa effects and could thus serve as a predictive tool for the anticoagulant potential of a new compound.

References

Jan 23, 1989·Journal of Theoretical Biology·M A Khanin, V V Semenov
Apr 11, 1971·The American Journal of Physiology·G G Spellman, H L Nossel
Nov 1, 1994·Annals of Internal Medicine·P S WellsJ Hirsh
Jul 1, 1994·Annals of Biomedical Engineering·S A Baldwin, D Basmadjian
Jun 30, 1998·Thrombosis Research·M A KhaninA E Kogan
Feb 7, 2001·Chest·J AnsellD Matchar
Jul 23, 2003·Journal of Thrombosis and Haemostasis : JTH·K G MannS Butenas
Feb 11, 2005·The Journal of Pharmacology and Experimental Therapeutics·Ashraf YassenMeindert Danhof
Jun 28, 2005·Journal of Thrombosis and Haemostasis : JTH·K Brummel-ZiedinsK G Mann
Oct 4, 2005·Clinical Pharmacology and Therapeutics·Dagmar KubitzaGeorg Wensing
Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Jun 29, 2007·International Journal of Clinical Pharmacology and Therapeutics·W MueckM Zuehlsdorf
Oct 4, 2008·Toxicon : Official Journal of the International Society on Toxinology·P P TanosS B Duffull
May 12, 2009·Archives of Cardiovascular Diseases·Nadia RosencherLeila Arnaout
Jun 12, 2009·Clinical Pharmacology and Therapeutics·T WajimaS B Duffull
Jan 28, 2010·BMC Systems Biology·Alexey M ShibekoFazoil I Ataullakhanov
Mar 9, 2010·Thrombosis Research·Anna Rosa CornoMichele Nichelatti
May 25, 2010·Journal of Thrombosis and Haemostasis : JTH·T OrfeoK G Mann
May 3, 2011·Nature Reviews. Drug Discovery·John Arrowsmith
Sep 8, 2012·Neural Networks : the Official Journal of the International Neural Network Society·Juan YuHaijun Jiang
Mar 16, 2013·Advances in Nutrition·Shelley McGuire
Mar 19, 2013·Drug Discovery Today·Göran Dahl, Tomas Akerud
Mar 26, 2013·American Journal of Clinical Pathology·Clifford M TakemotoThomas Kickler
Feb 20, 2014·Medicinal Research Reviews·Dong GuoLaura H Heitman
Aug 30, 2014·Clinics in Laboratory Medicine·Meyer Michel SamamaCharles Marc Samama
Nov 25, 2014·Clinical Pharmacology : Advances and Applications·Charles FrostFrank LaCreta
Jan 13, 2015·Clinical Pharmacokinetics·Charles E FrostFrank LaCreta
Feb 18, 2015·Current Opinion in Critical Care·Eric M LiottaAndrew M Naidech

❮ Previous
Next ❯

Citations

Jun 3, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Mirjam N TrameJerome T Mettetal
Sep 24, 2016·ACS Medicinal Chemistry Letters·Dong GuoAdriaan P IJzerman
Dec 12, 2019·The Journal of Pharmacology and Experimental Therapeutics·Violeta Balbas-MartinezIñaki F Troconiz

❮ Previous
Next ❯

Software Mentioned

MathWorks SimBiology toolbox
MATLAB
SimBiology
GetData Graph Digitizer

Related Concepts

Related Feeds

Blood Clotting Disorders

Thrombophilia includes conditions with increased tendency for excessive blood clotting. Blood clotting occurs when the body has insufficient amounts of specialized proteins that make blood clot and stop bleeding. Here is the latest research on blood clotting disorders.