A Drug-Drug Interaction Study to Evaluate the Impact of Simvastatin and Itraconazole on Erlotinib Pharmacokinetics in Rats by UPLC-MS/MS

Aim: The goal of our study was to investigate the effects of single-dose simvastatin and itraconazole application on the pharmacokinetics of erlotinib in rats. Methods: Twenty-one male Sprague-Dawley rats were randomly divided into 3 groups, including erlotinib combined with simvastatin, erlotinib combined with itraconazole and erlotinib alone groups. The rats were given a single dose of 2 mg/kg simvastatin, 15 mg/kg itraconazole or 0.5% sodium carboxymethyl cellulose followed by 12 mg/kg erlotinib. The concentration of erlotinib in rat plasma was determined by UPLC-MS/MS. As internal standard, tinidazole was used for chromatographic analysis on the Kinetex C-18 column (100x2.1 mm, 2.6 mu m). Results: Erlotinib was validated in the calibration range of 5-1000 ng/mL. The lower limit of quantification (LLOQ) was 5 ng/mL. The inter- and intra-day precisions for erlotinib were less than 10.56%, and the accuracies were in the range of 98.61-104.99%. The validated UPLC-MS/MS method was successfully applied to this study. Compared with the erlotinib alone group, the values of AUC(0-t), AUC(0-infinity), C-max, V-z/F and t(1/2) in the simvastatin group showed no statistical differences among pharmacokinetic parameters (P>0.05). However, the values of AUC(0-t), AUC(0-infinity) and C-max, in the itraconazole group were approximately 1.32-fold, 1.32-fold and 1.34-fold higher, and the CL/F was lower than those in the erlotinib alone group; the difference was statistically significant (P<0.05). Conclusion: Simvastatin had no significant effect on the pharmacokinetics of erlotinib, whereas co-administration of itraconazole considerably increased the exposure of erlotinib. Therefore, we should pay more attention to the potential drug-drug interaction to ensure safety in cancer patient treatment.