Model-Based Evaluation of the Warfarin-Sulfamethoxazole Drug-Drug Interaction

Warfarin exhibits complex drug-drug interactions (DDIs), particularly with sulfamethoxazole, which competitively inhibits cytochrome P450 2C-mediated metabolism of S-warfarin. This study developed a population pharmacokinetic-pharmacodynamic (PK-PD) model to evaluate the DDI of warfarin with different doses of sulfamethoxazole/trimethoprim using a model-based approach.

Male Wistar rats (n = 4 per group) received intravenous warfarin (400 μg/kg) with or without therapeutic or standard prophylactic doses of sulfamethoxazole/trimethoprim (200/40 mg/kg and 100/20 mg/kg, respectively). Plasma concentrations of S-warfarin and sulfamethoxazole and the prothrombin time international normalized ratio (PT-INR) were recorded. After developing a population PK-PD model of the interaction between S-warfarin and sulfamethoxazole, simulations were conducted with a target trough PT-INR of 2.0 at steady state. The required warfarin dose was compared between the WF alone, WF+TD-ST (ST 200/40 mg/kg), WF+SPD-ST (ST 100/20 mg/kg), and WF+LPD-ST (ST 20/4 mg/kg) groups.

Among the groups, the WF+TD-ST group exhibited the highest S-warfarin AUC_0-∞ (77.6 ± 9.3 μg × h/mL) and peak PT-INR (2.5 ± 0.6), indicating the greatest increase in both warfarin exposure and anticoagulant effect. Population PK-PD model simulations indicated that warfarin dose reductions of approximately 45%, 75%, and 85% were required as the sulfamethoxazole dose increased to maintain a target trough PT-INR of 2.0 at steady state. Our population PK-PD model quantified the warfarin-sulfamethoxazole DDI.

The proposed model supports model-based warfarin dosing during co-administration with different doses of sulfamethoxazole/trimethoprim.