Fluconazole bioequivalence study: Quantification by tandem mass spectrometry

To develop a new method for quantifying fluoconazole in human plasma and to compare the bioavailability of two fluconazole capsule formulations, an op en, 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 concentratio ns were analyzed using electrospray tandem mass spectrometry coupled to liq uid chromatography using multiple reaction monitoring mode. The pharmacokin etic parameters obtained for fluconazole after the administration of each f ormulation included the Area under the curve (AUC)((0-168h)), AUC((0-infini ty)), Cmax, Cmax/AUC((0-168h)). Tmax, elimination rate constant (Ke), and h alf-life (T-1/2). Within- and between-run imprecision was less than 2.3% an d 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 (F luconol; Libbs Farmaceutica Ltda, Sao Paulo, Brazil; Zoltec; Laboratorios P fizer Ltda., Sao 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 T-1/2, 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 analys is of fluconazole. Because the 90% CI AUC is within the interval proposed f or the Food and Drug Administration, we concluded that Fluconal is bioequiv alent to Zoltec in terms of absorption. The CV was 27.5% for the Cmax param eter, indicating that fluconazole's absorption rate is highly variable. The European Union Regulatory Agency accepts an interval of 70-143%, and becau se the 90% CI for Cmax is within the interval proposed for the European Uni on agency, we conclude that Fluconal is bioequivalent to Zoltec for the rat e of absorption.