None listed
Conditions
Brief summary
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.
Interventions
Arm: 1 The patients are randomly assigned with warfarin tablet brand A (reference) for 4 weeks then will be swapped over to warfarin tablet brand B (test) for next 4 weeks. The drug dose regimen are equal to the previous ones of the patients.
Arm 2: The patients are randomly assigned with warfarin tablet brand B (test) for 4 weeks then will be swapped over to warfarin tablet brand A (reference) for next 4 weeks. The drug dose regimen are equal to the previous ones of the patients.
The first wee
Arm: 1 The patients are randomly assigned with warfarin tablet brand A (reference) for 4 weeks then will be swapped over to warfarin tablet brand B (test) for next 4 weeks. The drug dose regimen are equal to the previous ones of the patients. Arm 2: The patients are randomly assigned with warfarin tablet brand B (test) for 4 weeks then will be swapped over to warfarin tablet brand A (reference) for next 4 weeks. The drug dose regimen are equal to the previous ones of the patients. The first week of the second warfarin brand treatment period is regarded as the washout period and time to get the second drug brand steady-state. Regarding that warfarin half-life is approximately 20-24 hours, one week period is considered sufficient as the washout period of the first brand and the steady-state for the second brand. The adherence is evaluated by tablet count on each visit, along with a medication and food diary given to the patients to record for their drug administration. Also warfarin concentration (total and free concentration) in plasma, and warfarin metabolites (4'-, 6-, 7-, 8-, and 10-hydroxywarfarin) concentration in urine will be analyzed by LC-MS/MS.
Sponsors
Therapeutcs Research Centre, University of South Australia
Study design
Allocation
Randomised controlled trial
Intervention model
Crossover
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age greater than or equal to 18 years 2. Receiving warfarin treatment 3. Clinically stable with the same dose of warfarin yielding a stable (less than 0.5 unit change over the lead-in period) of INR value that falls within the target therapeutic range (2.0 -3.0 or 2.5-3.5) for at least 6 weeks
Exclusion criteria
1. Age less than 18 years 2. Allergy to any ingredients in warfarin product 3. Pregnancy or breast feeding 4. Non-adherence tendency 5. Psychiatric disorder or dementia 6. Significant renal dysfunction (adjusted creatinine clearance calculated by Cockcroft-Gault equation < 60 mL/min) 7. Significant liver dysfunction (AST, ALT > 3 times of upper limits) 8. Excessive alcohol consumption 9. Taking any medications, food or dietary supplement that significantly interact with warfarin 10. Limited English communication proficiency
Outcome results
None listed