Fluoxetine bioequivalence study: Quantification of fluoxetine and norfluoxetine by liquid chromatography coupled to mass spectrometry

In this study the authors assessed the bioequivalence of two fluoxetine tab let formulations in 24 healthy volunteers of both sexes who received a sing le 20 mg dose of each fluoxetine formulation, and a new sensitive method fo r the quantification of fluoxetine and norfluoxetine in human plasma was de veloped. The study was conducted using an open, randomized, two-period cros sover design with a 1-week washout interval. Plasma samples were obtained o ver a 672-hour period. Plasma fluoxetine and norfluoxetine concentrations w ere analyzed by combined liquid chromatography coupled to mass spectrometry (LC-MS) with positive ion electrospray ionization using selected ion recor ding (SIR). Kolmogorov-Smirnov's test, histograms, probit plots, and the co rrelation between norfluoxetine AUC((0-infinity)) and puoxetine AUC((0-infi nity)) were used to analyze the population distribution. The limit of quant ification was 0.15 ng.ml(-1) and 0.50 ng.ml(-1) for both fluoxetine and nor fluoxetine, respectively Within- and between-run imprecision was less than 23% and 17%, respectively. The pharmacokinetic parameters obtained for fluo xetine and norfluoxetine after the administration of each formulation inclu ded AUC((0-672h)), AUC((0-infinity)), C-max, C-max/AUC((0-672h)), t(max), t (1/2), and Ke. The AUC values for fluoxetine were not consistent with a nor mal distribution, reflecting the existence of two different populations (po or and extensive metabolizers). The mean pharmacokinetic parameters for ext ensive fluoxetine metabolizers were 27.0 ng ml(-1) for C-max, 2064.0 ng h m l(-1) for AUC((0-infinity)), and 85.4 h t(1/2). The mean pharmacokinetic pa rameters for norfluoxetine (in extensive metabolizers only) were 2532.0 ng h ml(-1) for AUC((0-infinity)) and 8.4 ng ml(-1) for C-max. For puoxetine b ioequivalence, the 90% CI of the individual ratio geometric mean for Psiqui al(R)/Prozac(R) (including both extensive and poor metabolizers) was 101.6% to 121.1% for AUC((0-672h)) and 86.1% to 102.6% for C-max. For norfluoxeti ne, the 90% CI of the individual ratio geometric mean far Psiquial(R)/Proza c(R) (including both extensive and poor metabolizers) was 90.3% to 108.3% f or AUC((0-672h)) and 84.5% to 106.3% for C-max. The new method developed (L C-MS) presented high sensitivity, specificity and short chromatographic run for the quantification of both puoxetine and norfluoxetine in human plasma . Since both 90% CI for AUC and C-max geometric mean ratios were included i n the 80% to 125% interval proposed by the U.S. Food and Drug Administratio n, Psiquial(R) was considered bioequivalent to Prozac(R) according to both the rate and extent of absorption. The finding that there were no significa nt differences in the bioequivalence assessed by either fluoxetine or norfl uoxetine pharmacokinetic parameters indicates that future bioequivalence tr ials may be performed by quantifying puoxetine only Journal of Clinical Pha rmacology 1999;39:1053-1061 (C)1999 the American College of Clinical Pharma cology.