Warfarin maintenance dose adjustment with indirect pharmacodynamic model in rats

The purpose of the study was to adjust the individual maintenance dose of warfarin with a simple approach based on indirect pharmacodynamic model (IDR). Based on the distinct pharmacokinetic and pharmacodynamic features of warfarin, the relationship between the maintenance dose and the steady-state anticoagulation effect was simplified and an approach for the maintenance dose adjustment was proposed. According to the steady-state anticoagulation effect before and after multiple doses (0.1 mg kg^-1 day^-1), the optimal maintenance doses were predicted for the target anticoagulation effect (INR_target = 2.5), then the actual anticoagulation effect (prothrombin times, PT) on the 6th (8pm)\8th (8am)\10th (2pm) day after dose adjustment according the present method was compared with the target effects with a view of determination the feasibility and accuracy of the proposed approach. The proposed method was also used to adjust warfarin maintenance doses in the presence of metabolism inhibitor metronidazole. The results suggested that the proposed approach could appropriately achieve the target international normalized ratio (INR_target) when warfarin used alone or in combination with metronidazole, the actual INR values of three days were 2.69 ± 0.18 and 2.52 ± 0.22 (mean ± S.D.), respectively. The method provided a relatively simple and accurate strategy for warfarin maintenance dose adjustment.