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Who Needs Individual Bioequivalence Studies for Narrow Therapeutic Index Drugs? A Case for Warfarin
Author(s) -
Yacobi Avraham,
Masson Eric,
Moros Daniel,
Ganes Derek,
MSc Claude Lapointe,
Abolfathi Zohreh,
LeBel Marc,
Golander Yechiel,
Doepner Darlene,
Blumberg Tamar,
Cohen Yoram,
Levitt Barrie
Publication year - 2000
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912700022009558
Subject(s) - bioequivalence , warfarin , medicine , pharmacokinetics , crossover study , pharmacology , therapeutic index , replicate , cyp2c9 , drug , statistics , mathematics , placebo , alternative medicine , pathology , cytochrome p450 , metabolism , atrial fibrillation
Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of “switching,” an individual bioequivalence study involving a replicate‐design study and three “switchings” in healthy subjects was undertaken using the U.S.‐brand warfarin sodium tablet and a generic product. A randomized, single‐center, open‐label, single‐dose, four‐way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject‐by‐formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.