RESUMO
BACKGROUND AND OBJECTIVE: Erlotinib is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a reversible tyrosine kinase inhibitor that acts on the epidermal growth factor receptor and inhibits cell proliferation, growth, migration, invasion and survival. This study was performed for the subsequent marketing of a test erlotinib formulation in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy adult volunteers. METHODS: A total of 46 healthy male subjects were enrolled in a single-dose, randomized, open-label, two-period, two-sequence, crossover, bioequivalence study. During each treatment period, subjects received 150 mg of erlotinib in either the test or reference formulation. There was a 2-week washout period between each period. Blood samples were obtained 15 times during each period, before dosing and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72 and 96 h after oral administration. Plasma concentrations of erlotinib were determined using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C(max)), area under the plasma concentration-time curve to the last sampling time (AUC(t)), AUC from time zero to infinity (AUC(∞)), and time to reach C(max) (t(max)), were measured, and all treatment-emergent adverse events and their relationships with the study medications were recorded throughout the study. An additional analysis was performed to characterize the association between the cytochrome P450 (CYP) 1A1, CYP1A2 and CYP3A4 genotypes and the erlotinib pharmacokinetic parameters. RESULTS: A total of 41 subjects completed the study. There were no significant differences in the prevalence of adverse events between the two formulations, and there were no serious or unexpected adverse events during the study. Both formulations had very similar C(max), AUC, terminal half-life (t ½) and t(max) values. The 90% confidence intervals of the geometric least-squares mean ratios of the test to reference formulation were 1.09 (0.98-1.22) for C(max) and 1.10 (1.01-1.21) for AUCt. Statistical significance was observed between the CYP1A2*1M genotype and the erlotinib pharmacokinetic parameter, particularly C(max) (p = 0.015). CONCLUSIONS: This study suggests that the test and reference formulations of 150 mg erlotinib have similar pharmacokinetic characteristics. Both had no major safety issues and were well-tolerated. The test formulation met the regulatory criteria for assuming bioequivalence to the reference formulation for both AUCt and C max. The additional genetic analysis demonstrated that the major metabolic enzymes of erlotinib did not significantly affect erlotinib metabolism, with the exception of CYP1A2*1M.
