Capecitabine bioequivalence in healthy volunteers.

Capecitabine is a prodrug and is selectively activated by tumor cells to its cytotoxic moiety, 5-fluorouracil, by thymidine phosphorylase, which is generally expressed at high levels in tumors. Clinical and pharmacokinetic studies of capecitabine have been performed in patients with cancer. This study aims to evaluate the bioequivalence of two capecitabine formulations (150-mg tablet) using healthy male subjects under nonfasting conditions. The study was conducted as an open, randomized, three-period, semi-replicated design with three sequences (RRT, RTR, TRR) with a 1-week washout interval. The subjects were selected for the study after having their health status previously assessed by a clinical evaluation and laboratory tests (biochemical and hematological parameters, and urinalysis). A single capecitabine tablet (150 mg) was given in each occasion. Plasma capecitabine concentrations were analyzed by liquid chromatography coupled with tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The geometric mean and 90% confidence intervals (CI) of capecitabine/Xeloda® (T/R) percent ratio were 104.34% (98.74 - 110.25%) for AUClast, 103.06% (97.48 - 108.96%) for AUCinf, and 104.07% (88.13 - 122.90%) for Cmax. Since the 90% CI for Cmax, AUClast, and AUCinf ratios were all inside the 80 - 125% interval proposed by the US Food and Drug Administration Agency, it was concluded that the capecitabine formulation elaborated by Eurofarma Laboratórios Ltda. is bioequivalent to Xeloda® formulation for both the rate and the extent of absorption. The drug was well tolerated by the subjects, indicating that it is safe to perform capecitabine bioequivalence studies in healthy male subjects.
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An improved LC-MS/MS method for quantitation of indapamide in whole blood: application for a bioequivalence study.

An improved LC-MS/MS method for the quantitation of indapamide in human whole blood was developed and validated. Indapamide-d3 was used as internal standard (IS) and liquid-liquid extraction was employed for sample preparation. LC separation was performed on Synergi Polar RP-column (50 × 4.6 mm i.d.; 4 µm) and mobile phase composed of methanol and 5 mm aqueous ammonium acetate containing 1 mm formic acid (60:40), at flow rate of 1 mL/min. The run time was 3.0 min and the injection volume was 20 µL. Mass spectrometric detection was performed using electrospray ion source in negative ionization mode, using the transitions m/z 364.0 → m/z 188.9 and m/z 367.0 → m/z 188.9 for indapamide and IS, respectively. Calibration curve was constructed over the range 0.25-50 ng/mL. The method was precise and accurate, and provided recovery rates >80% for indapamide and IS. The method was applied to determine blood concentrations of indapamide in a bioequivalence study with two sustained release tablet formulations. The 90% confidence interval for the geometric mean ratios for maximum concentration was 95.78% and for the area under the concentration-time curve it was 97.91%. The tested indapamide tablets (Eurofarma Laboratórios S.A.) were bioequivalent to Natrilix®, according to the rate and extent of absorption.