Why the study?
DOACs have a steep exposure-response relationship for bleeding risk where small exposure changes may cause bleeding, necessitating evaluation of how critical formulation parameters affect the pharmacokinetics, safety, and efficacy of generic DOACs.
PBPK modeling demonstrates that dabigatran etexilate exposure is highly sensitive to supersaturation ratio and precipitation kinetics, which has implications for the safety and efficacy of generic formulations.
PBPK model enables evaluation of generic DOAC formulation effects on exposure; leaves open clinical impact on bleeding versus stroke risk.
The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically-based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.
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Farhan et al. (2021) studied this question.
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