Who needs individual bioequivalence studies for narrow therapeutic index drugs? A case for warfarin

lWarfarin is, among drugs, considered to have a narrow therapeutic index fo r which individual bioequivalence has been suggested. To establish the prop riety of "switching," an individual bioequivalence study involving a replic ate-design study and three "switchings" in healthy subjects was undertaken using the U.S.-brand warfarin sodium tablet and a generic product A randomi zed single-center, open-label, single-dose, four-way crossover replicate bi oequivalence study was performed in 24 healthy male Volunteers in which eac h 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 individua l 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 bioequi valence assessment did not show a subject-by-formulation interaction, nor d id it add value to the bioequivalence assessment of warfarin. (C) 2000 the American College of Clinical Pharmacology.