Abstract WP273: Reversal of Dabigatran’s Anticoagulant Activity in the Monkey by a Specific Antidote and Pharmacokinetic and Pharmacodynamic Modeling
The objective of this study is to determine pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran and its antidote (a humanized Fab against dabigatran) in the monkey and to develop a combined mechanistic mathematical model to describe the data. Rhesus monkeys (n = 2/group) received either 12 mg/kg/day of dabigatran etexilate (DE) or vehicle orally on Days 1-4, 15-18 and 29-32 with a single IV dose of the antidote at 30, 90 and 175 mg/kg administered 90 minutes after DE on Days 4, 18 and 32. PK parameters of the antidote and sum dabigatran (dabigatran plus its glucuronides) were determined after measurements of plasma concentrations. Coagulation activity was measured using a diluted thrombin time assay. The PK of the antidote were not affected by dabigatran. Clearance of the antidote was low (0.87 mL/min/kg) and steady-state volume of distribution was small (0.06 L/kg), indicating that the antidote was mostly restricted to plasma. The plasma profile of the antidote was bi-phasic with a short initial phase t1/2 of 0.4 hour (h) and a terminal phase t1/2 of 4.3 h. Complete reversal of dabigatran’s anticoagulant activity was observed immediately after antidote dosing at all 3 dose levels as measured by the diluted thrombin time assay, and the degree to which this reversal effect was maintained over an extended period (24 h) was dose-dependent. A mechanistic ordinary differential equation model, based on the mass action kinetics for describing the distribution, binding and elimination of dabigatran and its antidote, was developed by combining the PK models for dabigatran and the antidote and adding the binding interaction (1:1 stoichiometry) between the two compounds. The combined PK/PD model of dabigatran and antidote was able to describe the in vivo PK/PD data observed in monkeys. In conclusion, the antidote successfully reversed the anticoagulant activity of dabigatran in the monkey in a dose-dependent manner, and our combined mathematical model accurately describes monkey PK/PD data of sum dabigatran and its antidote. Insights gained from this model will be used to guide model development for clinical trials.
- © 2012 by American Heart Association, Inc.