PHARMACOKINETIC INTERACTION AFTER ORAL COADMINISTRATION OF CLARITHROMYCIN AND THE TYROSINE KINASE INHIBITOR LAPATINIB IN RATS.

Lapatinib is a tyrosine kinase inhibitor used to treat patients with locally advanced or metastatic breast cancer exhibiting overexpression of the human epidermal growth factor receptor 2 (HER2 receptor, ErbB2). Preclinical and clinical studies suggest that lapatinib is mainly metabolized by CYP3A4, therefore the study in an animal model was designed to investigate the pharmacokinetic interaction of lapatinib and clarithromycin, a well-known CYP3A4 inhibitor. The rats were subjected to one of the two study groups: lapatinib + clarithromycin (I_Lap+Clar; n = 6), and lapatinib + placebo (II_Lap; n = 6). The animals were treated with lapatinib in the oral single dose of 100 mg/kg. The antibiotic was administered orally at a dose of 25 mg/kg. Blood sampling was performed until 30 hours after dosing for pharmacokinetic assays. Plasma concentrations of lapatinib were measured by liquid chromatography-mass spectrometry. The comparison of lapatinib maximum concentration and area under the concentration-time curve in the I_Lap+Clar with the control group II_Lap gave the ratios of 1.38 (90% confidence interval (CI)) (1.14; 1.68) and 1.16 (0.75; 1.79), respectively. A statistically significant difference between analyzed groups was revealed only for maximum concentration (p = 0.0107). Single oral administration of clarithromycin significantly increased the concentration of lapatinib in rats, therefore caution should be taken during concomitant treatment with this macrolide and the tyrosine kinase inhibitor in patients. [ABSTRACT FROM AUTHOR]