In this study, the authors assessed the bioequivalence of two fluoxetine tablet formulations in 24 healthy volunteers of both sexes who received a single 20 mg dose of each fluoxetine formulation, and a new sensitive method for the quantification of fluoxetine and norfluoxetine in human plasma was developed. The study was conducted using an open, randomized, two-period crossover design with a 4-week washout interval. Plasma samples were obtained over a 672-hour period. Plasma fluoxetine and norfluoxetine concentrations were analyzed by combined liquid chromatography coupled to mass spectrometry (LC-MS) with positive ion electrospray ionization using selected ion recording (SIR). Kolmogorov-Smirnov's test, histograms, probit plots, and the correlation between norfluoxetine AUC((0-∞)) and fluoxetine AUC((0-∞)) were used to analyze the population distribution. The limit of quantification was O.15 ng ·ml-1 and O.50 ng ·ml-1 for both fluoxetine and norfluoxetine, respectively. Within- and between-run imprecision was less than 13% and 17%, respectively. The pharmacokinetic parameters obtained for fluoxetine and nor-fluoxetine after the administration of each formulation included AUC((0·672h)), AUC((0-∞)), C(max), C(max)/AUC((0·672h)), t(max), t( 1/2 ), and Ke. The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of two different populations (poor and extensive metabolizers). The mean pharmacokinetic parameters for extensive fluoxetine metabolizers were 27.0 ng ml-1 for C(max), 2064.0 ng h ml-1 for AUC((0-∞)) and 85.4 h t( 1/2 ). The mean pharmacokinetic parameters for norfluoxetine (in extensive metabolizers only) were 2532.0 ng h ml-1 for AUC((0-∞)) and 8.4 ng ml-1 for C(max). For fluoxetine bioequivalence, the 90% CI of the individual ratio geometric mean for Psiquial√RProzac® (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). Fornorfluoxetine, the 90% CI of the individual ratio geometric mean for Psiquial®/Prozac® (including both extensive and poor metabolizers) was 90.3% to 108.3% for AUC((0.672h) and 84.5% to 106.3% for C(max). The new method developed (LC-MS) presented high sensitivity specificity and short chromatographic run for the quantification of both fluoxetine and norfluoxetine in human plasma. Since both 90% CI for AUC and C(max) geometric mean ratios were included in the 80% to 125% interval proposed by the U.S. Food and Drug Administration, Psiquial® was considered bioequivalent to Prozac® according to both the rate and extent of absorption. The finding that there were no significant differences in the bioequivalence assessed by either fluoxetine or norfluoxetine pharmacokinetic parameters indicates that future bioequivalence trials may be performed by quantifying fluoxetine only. (C) 1999 the American College of Clinical Pharmacology.

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

CORSO, GAETANO;
1999

Abstract

In this study, the authors assessed the bioequivalence of two fluoxetine tablet formulations in 24 healthy volunteers of both sexes who received a single 20 mg dose of each fluoxetine formulation, and a new sensitive method for the quantification of fluoxetine and norfluoxetine in human plasma was developed. The study was conducted using an open, randomized, two-period crossover design with a 4-week washout interval. Plasma samples were obtained over a 672-hour period. Plasma fluoxetine and norfluoxetine concentrations were analyzed by combined liquid chromatography coupled to mass spectrometry (LC-MS) with positive ion electrospray ionization using selected ion recording (SIR). Kolmogorov-Smirnov's test, histograms, probit plots, and the correlation between norfluoxetine AUC((0-∞)) and fluoxetine AUC((0-∞)) were used to analyze the population distribution. The limit of quantification was O.15 ng ·ml-1 and O.50 ng ·ml-1 for both fluoxetine and norfluoxetine, respectively. Within- and between-run imprecision was less than 13% and 17%, respectively. The pharmacokinetic parameters obtained for fluoxetine and nor-fluoxetine after the administration of each formulation included AUC((0·672h)), AUC((0-∞)), C(max), C(max)/AUC((0·672h)), t(max), t( 1/2 ), and Ke. The AUC values for fluoxetine were not consistent with a normal distribution, reflecting the existence of two different populations (poor and extensive metabolizers). The mean pharmacokinetic parameters for extensive fluoxetine metabolizers were 27.0 ng ml-1 for C(max), 2064.0 ng h ml-1 for AUC((0-∞)) and 85.4 h t( 1/2 ). The mean pharmacokinetic parameters for norfluoxetine (in extensive metabolizers only) were 2532.0 ng h ml-1 for AUC((0-∞)) and 8.4 ng ml-1 for C(max). For fluoxetine bioequivalence, the 90% CI of the individual ratio geometric mean for Psiquial√RProzac® (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). Fornorfluoxetine, the 90% CI of the individual ratio geometric mean for Psiquial®/Prozac® (including both extensive and poor metabolizers) was 90.3% to 108.3% for AUC((0.672h) and 84.5% to 106.3% for C(max). The new method developed (LC-MS) presented high sensitivity specificity and short chromatographic run for the quantification of both fluoxetine and norfluoxetine in human plasma. Since both 90% CI for AUC and C(max) geometric mean ratios were included in the 80% to 125% interval proposed by the U.S. Food and Drug Administration, Psiquial® was considered bioequivalent to Prozac® according to both the rate and extent of absorption. The finding that there were no significant differences in the bioequivalence assessed by either fluoxetine or norfluoxetine pharmacokinetic parameters indicates that future bioequivalence trials may be performed by quantifying fluoxetine only. (C) 1999 the American College of Clinical Pharmacology.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11369/7934
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