An ordinary differential equation-based integrated pharmacokinetic–pharmacodynamic model for predicting anticoagulant responses to warfarin and diphacinone across rodent and bat species

Abstract

Interspecies differences in sensitivity to anticoagulant compounds remain an important issue in veterinary toxicology and wildlife risk assessment. In the present study, we developed an integrated pharmacokinetic–pharmacodynamic (PK/PD) model to quantitatively compare anticoagulant responses between rats and bats, linking hepatic exposure to vitamin K epoxide reductase (VKOR) inhibition and subsequent changes in prothrombin time–international normalized ratio (PT-INR). Species-specific pharmacokinetic parameters were estimated from experimental concentration–time data and incorporated into a mechanistic turnover model describing VKOR activity and clotting factor synthesis. The model reproduced dose-dependent PT-INR prolongation in rats and successfully described the delayed and attenuated anticoagulant responses observed in bats. Sensitivity analyses identified hepatic clearance (CLh), hepatic distribution volume (Vh), and the half-maximal inhibitory concentration for VKOR (IC₅₀) as key determinants of PT-INR responses, with a smaller contribution from baseline coagulation turnover. In addition, structure-based binding affinity estimates were explored as surrogate indicators of inhibitory potency. Although computational affinity scores qualitatively reflected relative anticoagulant strength, substituting these scores for experimentally derived inhibitory parameters reduced predictive accuracy in some resistant species, highlighting the current limitations of structure-only approaches. These findings demonstrate that mechanistic PK/PD integration provides a quantitative framework for evaluating species differences in anticoagulant toxicity and may support veterinary risk assessment and wildlife protection strategies.