Abstract
Objective: The aim of the study was to explore the association of pharmacokinetic variability and pharmacogenomics with the bioequivalence of orally administered gefitinib (Iressa®, AstraZeneca) provided by three sponsors in healthy subjects.Methods: The study designs were randomized, open-label, and two-period crossover studies in both fasting and fed healthy subjects. In one fasting study, the sample size was enlarged from 30 to 60 for the failing study. Each study subject received a 250-mg gefitinib tablet with a 21-day washout. The plasma concentrations were measured using LC-MS/MS, and pharmacokinetic parameters were determined by noncompartmental methods. Genetic analyses of CYP3A4, CYP3A5, and CYP2D6 alleles were carried out by the polymerase chain reaction (PCR).Results: Two hundred and sixty healthy male subjects were enrolled. The median maximum plasma concentration (Tmax) was 4–5 h, and the mean elimination half-life (t1/2) was 18–26 h. The maximum plasma concentration (Cmax) and area under the curve (AUC) increased but Tmax and t1/2 were unaffected by the intake of high-fat food. Three fed and two fasting studies achieved a plausible bioequivalence. The intake of high-fat food decreased the intra-subject variability significantly. In addition, CYP2D6 was associated with gefitinib exposure and may contribute to the high inter-subject variability, but it did not influence the bioequivalence result.Conclusions: Gefitinib is well tolerated, and the bioequivalence is easier to achieve under fed conditions compared to fasting conditions. The 90% confidence interval (CI) of geometric mean ratio (GMR) can be narrowed when the sample size is enlarged without changing the formulation-related technology.
Highlights
Gefitinib (Iressa R, ZD1839, AstraZeneca) is a highly selective and an orally active small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)
It was observed that gefitinib was absorbed slowly, with the peak plasma level occurring at 4–5 h after the dose and coinciding with the time of maximum plasma concentration (Tmax) of cancer patients (3–7 h)
Polymorphisms in various metabolic enzymes and/or transport proteins may contribute to the high inter-coefficient of variation (CV) (Cantarini et al, 2008)4 We found that CYP2D6 gene polymorphisms in studies 3 and 5 could be associated with the exposure, and a major mutation occurred in the intron variant region
Summary
Gefitinib (Iressa R , ZD1839, AstraZeneca) is a highly selective and an orally active small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). With the end of the patent protection period of the inventor’s product, bioequivalence studies have been designed and reported to investigate and compare the pharmacological features of the drug with different formulations pertaining to the extent and rate of absorption of the active ingredient. To this end, in order to corroborate the therapeutic similarity between two drug products incorporating the same active ingredient, bioequivalence data are always crucial. The determination of bioequivalence depends on comparing the rate and the extent of absorption of the product under study (Test, T) with the original product (Reference, R) (Karalis et al, 2012)
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