Effective Removal of Dabigatran by Idarucizumab or Hemodialysis: A Physiologically Based Pharmacokinetic Modeling Analysis

Abstract

Background: Application of idarucizumab and hemodialysis are options to reverse the action of the oral anticoagulant dabigatran in emergency situations. Objectives: The objectives of this study were to build and evaluate a mechanistic, whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of idarucizumab, including its effects on dabigatran plasma concentrations and blood coagulation, in healthy and renally impaired individuals, and to include the effect of hemodialysis on dabigatran exposure. Methods: The idarucizumab model was built with the software packages PK-Sim® and MoBi® and evaluated using the full range of available clinical data. The default kidney structure in MoBi® was extended to mechanistically describe the renal reabsorption of idarucizumab and to correctly reproduce the reported fractions excreted into urine. To model the PD effects of idarucizumab on dabigatran plasma concentrations, and consequently also on blood coagulation, idarucizumab-dabigatran binding was implemented and a previously established PBPK model of dabigatran was expanded to a PBPK/PD model. The effect of hemodialysis on dabigatran was implemented by the addition of an extracorporeal dialyzer compartment with a clearance process governed by dialysate and blood flow rates. Results: The established idarucizumab-dabigatran-hemodialysis PBPK/PD model shows a good descriptive and predictive performance. To capture the clinical data of patients with renal impairment, both glomerular filtration and tubular reabsorption were modeled as functions of the individual creatinine clearance. Conclusions: A comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy.