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 (8 pm)\8th (8 am)\10th (2 pm) 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.
Cao
Yan-Guang
YG
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
Liu
Xiao-Quan
XQ
Chen
Yuan-Cheng
YC
Hao
Kun
K
Wang
Guang-Ji
GJ
D000284:Administration, Oral; D000465:Algorithms; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D019934:International Normalized Ratio; D008297:Male; D008795:Metronidazole / Q000008:administration & dosage / Q000494:pharmacology; D008954:Models, Biological; D011517:Prothrombin Time / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014859:Warfarin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000925:Anticoagulants; D004791:Enzyme Inhibitors; D008795:Metronidazole; D014859:Warfarin