Moricizine bioavailability via simultaneous, dual, stable isotope administration: Bioequivalence implications

The relative bioavailability of a 200 mg film-coated tablet of [C-12]morici zine . HCl in comparison to a 200 mg [C-13(6)] moricizine . HCl oral soluti on was determined after simultaneous administration to 8 young healthy male subjects. Concentrations of [C-12]moricizine . HCl and [C-13(6)]moricizine . HCl were determined by thermospray liquid chromatography-mass spectromet ry (LC-MS) using [H-2(11)]moricizine . HCl as the internal standard. The me an absorption and disposition parameters of the tablet versus the solution were the following (% CV): maximum concentration, 0.83 (39%) versus 0.79 (3 9%) mu g/mL; time of maximum concentration, 0.81 (40%) versus 0.65 (28%) ho urs; area under the concentration-time curve (AUC), 1.58 (39%) versus 1.49 (37%) mu g . h/mL; apparent oral clearance, 150.7 (52%) versus 158.1 (50%) L/h; and t(1/2), 1.9 (42%) versus 1.9 (42%) hours. The AUC for the tablet a veraged 106% of the solution, which likely reflects a greater first-pass ef fect with the oral solution. Partitioning sources of variation confirmed th e low (< 6%) intrasubject coefficient of variation (cv(epsilon)) afforded v ia the single-period dual-isotope design. In contrast, a previous study usi ng the conventional two-period crossover design determined the cv(epsilon) about moricizine metrics to be in excess of 30%, resulting in classificatio n of this drug as having highly variable absorption. The results of this st udy further illustrate the benefits of dual, stable isotopes to assess bioa vailability and bioequivalence. This paradigm results in a reduction in exp erimental time and subject inconvenience and lower costs in comparison with the standard crossover study. Perhaps most important is the improved stati stical power for the evaluation of bioavailability or bioequivalence in the absence of period and sequence effects that confound the assessment of int rasubject variation in the standard crossover design. Journal of Clinical P harmacology, 1999;39:817-825 (C) 1999 the American College of Clinical Phar macology.