Bioequivalence study of two formulations of 100 mg capsule of itraconazole-Quantification by tandem mass spectrometry

摘要

The purpose of this study is to compare the bioavailability of two itraconazole (CAS 84625-61-6) capsule formulations. An open, randomized, two-period crossover study with a 7-day washout interval was conduced in 32 healthy volunteers. The plasma samples were obtained up to 96 h after drug administration. A sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of itraconazole in human plasma. Itraconazole and ketocona-zole (internal standard) were extracted from the plasma by liquid-liquid extraction using diethylether: dichloromethane (70:30) as extraction solvent and separated on a C_8 analytical column (150 mm x 4.6 mm I.D.) maintained at 40 degC. The elution was performed by a constant flow rate of 1.2 mL/min and the mobile phase consisted of acetonitrile and acetic acid 0.1 % (85:15 v/v). The mass spectrometer equipped with an electrospray source in positive mode, was set up in multiple reaction monitoring, to detect parent -> product ion 705.0 -> 392.0 (itraconazole) and 531.0 -> 81.70 (ketoconazole). The chromatographic separation was obtained within 3.5 min and was linear in the concentration range of 5 to 600 ng/mL. Bioequivalence between the products was determined by calculating 90 % confidence intervals for the ratio of C_(max) (95.02%-109.48 %), AUC_(0-t) (81.41%-107.77%) and AUC(0-inf) (80.85 %-106.86 %). These values for the test and reference products are within the 80-125 % interval, proposed by FDA and EMEA. It was concluded that the proposed method was successfully applied to a pharmacokinetic study in healthy human volunteers, and results showed that the two itraconazole formulations are bioequivalent in their rate and extent of absorption.