Journal of Bioequivalence & Bioavailability

Abstract

The use of Healthy Volunteers to Evaluate Bioequivalence of Antineoplasic Drugs: Pilot Studies with Capecitabine

Gustavo Duarte Mendes, Tainah Babadopulos, Lu Shi Chen, Jaime O. Ilha, Jos? C?ssio de Almeida Magalh?es, Khalid Alkharfy and Gilberto De Nucci

Capecitabine is a prodrug, 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 pharmacokinetics studies for capecitabine are perfomed in patients with cancer. The objective of the study was to evaluate the safety of a bioequivalence study (150 mg tablet) using healthy male volunteers under fasting and non-fasting conditions. The study was conducted with an open, randomized, two-period crossover design in a 2-week washout interval without food. After the study without food was completed, a new protocol was submitted to the Ethics Committee to evaluate the study with food. The volunteers 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 (150mg) was given in each interment. An extra laboratory analysis was performed one week after the first administration of the drug for the safety of the subjects. Plasma capecitabine concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (HPLC/MS/MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). The pharmacokinetic parameters were 529.38 (±265.22) and 462.88 (±425.85) ng.mL -1 for C max , 262.31 (±75.34) and 300.49 (±91.51) ng.hr.mL -1 for AUC last , and 0.66 (range 0.5 – 1.25) hr and 1.0 (range 0.33 – 1.33) hr for T max , without and with food, respectively, for the reference formulation. The intra-subject CV were 42.6% and 76.3% for C max and 9.64% and 20.3% for AUC last without and with food, respectively. The drug was well tolerated by the volunteers, and they presented no adverse reactions. The biochemical and hematological parameters presented no clinically relevant alterations. Our results indicate that it is safe to perform capecitabine bioequivalence studies in healthy male volunteers.