Xuan Zhou (1), Dymphy R.H. Huntjens (2), Ron AHJ. Gilissen (1)
(1) Department of Pharmacokinetics, Metabolism and Dynamics, Discovery Sciences, Janssen, Belgium, (2) Model-Based Drug Development, Janssen, Belgium.
Objectives: To investigate the application of an integrated pharmacokinetics (PK), drug-target binding kinetic (BK) and systems biology model to predict the anticoagulation effects of a factor Xa (FXa) inhibitor–rivaroxaban in healthy subjects, and to use this model to compare the effects of FXa inhibitors with different binding properties.
Methods: The systems model consists of 55 ordinary differential equations (55 species, 89 reactions, 139 kinetic parameters) that are based on the chemical kinetic theory. The simulation of drug concentration after multiple oral doses (5, 10, 20 and 30 mg twice daily) was conducted based on the reported two-compartment PK model with 1st order absorption for rivaroxaban [1]. The predictions of prothrombin time (PT) and activated partial thromboplastin time (aPTT) were based on the connection of free drug concentration, target binding kinetics and systems biology model. A sensitivity analysis was performed to evaluate the impact of individual parameter and species on the interested state variables. To verify these results, several simulations for rivaroxaban were conducted whereby binding kinetic parameters were varied.
Results: From the simulations, rivaroxaban prolonged PT and aPTT in concentration-dependent, incremental manner through its inhibition of free and bound FXa. The predictions were in agreement with observed published data [2]. The sensitivity analysis indicated that both target binding kinetics (kon and koff for drug-FXa interaction) and drug concentration have high sensitivity on the response of PT and aPTT. Remarkable changes were observed in the simulated time profiles of PT and aPTT when kon and koff were varied 100-fold separately. This indicates the importance of binding kinetics on the pharmacodynamics effects.
Conclusions: The current model predicts the clotting time reasonably well and the role of pharmacokinetics and binding kinetics was further highlighted by sensitivity analysis and simulations. We believe that this model represents a good starting point and has potential to serve as a tool for new compound and or target selection for the management of coagulation.
References:
[1] Mueck W BM, Kubitza D, Voith B, Zuehlsdorf M. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban-an oral, direct factor xa inhibitor-in healthy subjects. Int J Clin Pharmacol Ther 2007, 45(6): 10.
[2] Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939-an oral, direct Factor Xa inhibitor-after multiple dosing in healthy male subjects. European journal of clinical pharmacology 2005, 61(12): 873-880.
Reference: PAGE 24 (2015) Abstr 3326 [www.page-meeting.org/?abstract=3326]
Poster: Drug/Disease modeling - Other topics