A comparative bioequivalence study of warfarin brands in cardiovascular patients

Substitution of an innovator to a generic drug product has been continuously rising. In the US, approximately $8 billion to $10 billion is the average cost saving per year of brand substitution and the generic drug prescription has increased from 19% in 1984 to 60-70% in 2009. The increase in drug brand substitution is a call for scientific attention of the appropriateness of available bioequivalence (BE) study guidelines at present. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same. The conclusion of BE studies is based on the assumption that if the test and reference drug products exhibit similar in vitro (i.e. acceptable drug content, similar dissolution/release profile) and in vivo performance (i.e. acceptable bioavailability), these drug products should possess therapeutic equivalence which includes efficacy and safety. However, because bioequivalence studies are conducted in healthy volunteers, these studies may or may not provide definitive evidence to guarantee the therapeutic equivalence in patients. This study aims to compare efficacy and safety of two warfarin products marketed in Australia, namely Coumadin or Marevan. The study design is a randomized, open-label, two-way, two-period, crossover study. A total of 50 patients who are prescribed with either brand of warfarin and clinically stable will be recruited in accordance with the inclusion and exclusion criteria. The patients will be allocated as the assigned randomized treatment sequence into 2 groups. For the first 4 weeks, Group I will start with Coumadin and Group II will start with Marevan. Then the participants will be crossed over to the other brand for another 4 weeks. Participant blood samples will be collected at baseline and weekly until the end of the study. Total and free racemic, R- and S-warfarin enantiomer concentration in plasma, as well as 4',6,7,8, and 10hydroxywarfarin metabolites in urine will be quantified by LC MS/MS. The efficacy of the two warfarin brands will be compared by evaluating International Normalized Ratio (INR) values, warfarin dose variation, mean warfarin dose to achieve target INR, area under the plasma concentrationtime curve, and warfarin metabolites to drug ratio. The safety profile evaluation will be achieved by recording any adverse drug.