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-infinity) and fluoxetine AUC(0-infinity) were used to analyze the population distribution. The limit of quantification was 0.15 ng.ml-1 and 0.50 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 norfluoxetine after the administration of each formulation included AUC(0-672 h), AUC(0-infinity), Cmax, Cmax/AUC(0-672 h), tmax, t1/2, 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 Cmax, 2064.0 ng h ml-1 for AUC(0-infinity), and 85.4 h t1/2. The mean pharmacokinetic parameters for norfluoxetine (in extensive metabolizers only) were 2532.0 ng h ml-1 for AUC(0-infinity) and 8.4 ng ml-1 for Cmax. For fluoxetine bioequivalence, the 90% CI of the individual ratio geometric mean for Psiquial/Prozac (including both extensive and poor metabolizers) was 101.6% to 121.1% for AUC(0-672 h) and 86.1% to 102.6% for Cmax. For norfluoxetine, 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(0-672 h) and 84.5% to 106.3% for Cmax. 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 Cmax 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.
To develop a new method for quantifying fluoconazole in human plasma and to compare the bioavailability of two fluconazole capsule formulations, an open, randomized, two-period crossover study with a one-week washout interval was conducted in 24 healthy volunteers. Plasma samples were obtained up to 168 hours after drug administration and the serum fluconazole concentrations were analyzed using electrospray tandem mass spectrometry coupled to liquid chromatography using multiple reaction monitoring mode. The pharmacokinetic parameters obtained for fluconazole after the administration of each formulation included the Area under the curve (AUC)(0-168h), AUC(0-infinity), Cmax, Cmax/AUC(0-168h), Tmax, elimination rate constant (Ke), and half-life (T1/2). Within- and between-run imprecision was less than 2.3% and 8.2%, respectively. Inaccuracy within and between runs was -1.5% and -9.7%, respectively. The pharmacokinetic parameters for bioequivalence showed a normal distribution, and the variance of AUC(0-168h), AUC(0-infinity), and Cmax were homoscedastic. The geometric mean for the Fluconal/Zoltec (Fluconal; Libbs Farmacêutica Ltda, São Paulo, Brazil; Zoltec; Laboratórios Pfizer Ltda., São Paulo, Brazil) individual percent ratio was 94.9% for AUC(0-168h), 94.7% for AUC(0-infinity), 80.1% for Cmax, 102.6% for Ke, 97.5% for T1/2, and 0.93 for Tmax (arithmetic mean of individual differences). We have developed a method in which liquid chromatography is coupled with electrospray tandem mass spectrometry to improve the pharmacokinetic analysis of fluconazole. Because the 90% CI AUC is within the interval proposed for the Food and Drug Administration, we concluded that Fluconal is bioequivalent to Zoltec in terms of absorption. The CV was 27.5% for the Cmax parameter, indicating that fluconazole's absorption rate is highly variable. The European Union Regulatory Agency accepts an interval of 70-143%, and because the 90% CI for Cmax is within the interval proposed for the European Union agency, we conclude that Fluconal is bioequivalent to Zoltec for the rate of absorption.
Short-term treatment with omeprazole in H. pylori- positive volunteers reduces the amount of metronidazole transferred from plasma to gastric juice. This seems to occur in a pH-independent form.
The aim of the study was to assess the bioequivalence of two different diclofenac (CAS 15307-86-5) formulations (diclofenac free acid suspension as test formulation and diclofenac resinate suspension, Cataflam, as reference formulation) in 24 healthy volunteers. After an overnight fast, the volunteers received a single oral dose (50 mg) of each formulation, following an open, randomized, two-period crossover design, with a fourteen-day washout interval between doses. Serum samples were obtained over a 24-h interval post-dosing, and were analysed for their diclofenac content by HPLC-UV. No adverse effect was reported for any of the formulations administered. Geometric mean test/reference individual ratios were: 92.8% for AUC(0-24 h), 93.2% for AUC(0-infinity), 117.2% for Cmax, 131.0% for Ke and 76.2% for T1/2. The variability of Cmax parameter expressed as CV was greater than 25%. Since the 90% CI for AUC(0-24 h) mean ratio were within the 80-125% interval proposed by the Food and Drug Administration, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for the extent of absorption. Since the European Community Agency accepts a 90% CI for Cmax of 70-143%, it can be concluded that diclofenac free acid formulation is bioequivalent to diclofenac resinate formulation for both the rate and the extent of absorption after single dose administration.
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