title: Bioequivalence study of two formulations of 100 mg capsule of itraconazole. Quantification by tandem mass spectrometry.
abstract: 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 ketoconazole (internal standard) were extracted from the plasma by liquid-liquid extraction using diethylether : dichloromethane (70 : 30) as extraction solvent and separated on a C8 analytical column (150 mm x 4.6 mm I.D.) maintained at 40 degrees C. 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 --> production 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.
authors.affiliation: BIOCINESE - Biopharmaceutical Studies Center, Toledo, PR, Brazil biocinese@biocinese.com.br
authors.forename: Josélia Larger
authors.initials: JL
authors.lastname: Manfio
authors.forename: Maurício Bedin
authors.initials: MB
authors.lastname: dos Santos
authors.forename: Wagner Alex Jann
authors.initials: WA
authors.lastname: Favreto
authors.forename: Anelise
authors.initials: A
authors.lastname: Weich
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Pugens
authors.forename: Carmen Maria
authors.initials: CM
authors.lastname: Donaduzzi
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D017964:Itraconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry; D013810:Therapeutic Equivalency; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D002214:Capsules; D017964:Itraconazole