A Two-Sequence, Four-Period, Crossover, Replicate Study to Demonstrate Bioequivalence of Warfarin Sodium Tablet in Healthy Chinese Subjects Under Fasting and Fed Conditions

Warfarin is a narrow therapeutic index anticoagulant drug, and several generic formulations have been approved worldwide. However, there has been no report evaluating the bioequivalence of warfarin sodium according to US Food and Drug Administration draft guidance. We designed a 2-sequence and 4-period crossover study to compare the pharmacokinetic profile and assess bioequivalence between the test warfarin sodium tablet and reference product Coumadin (2.5 mg) in 56 healthy Chinese subjects under fasting and fed conditions. The plasma concentration of warfarin was analyzed by a validated liquid chromatography-tandem mass spectrometry assay, and the reference-scaled procedure was used to determine bioequivalence for the pharmacokinetics parameters. The results showed that the point estimate of geometric mean ratios of C-max and AUC(0-t) for warfarin were 103.21% and 99.31%, respectively, in the fasting condition and 100.62% and 98.98%, respectively, in the fed condition, and the 90% confidence intervals were all within the range of 90.00%-111.11%. The upper limit of the 90% confidence interval of estimated within-subject variation ratios of the test and reference products was 1.33 for C-max and 2.22 for AUC(0-t) under the fasting condition and 1.68 for C-max and 2.15 for AUC(0-t) under the fed condition. Overall, bioequivalence of the 2 warfarin sodium products was demonstrated.