Drug Design, Development and Therapy (Oct 2023)
A Drug–Drug Interaction Study to Evaluate the Impact of Simvastatin and Itraconazole on Erlotinib Pharmacokinetics in Rats by UPLC-MS/MS
Abstract
Zaiwen Fan,1 Xiaonan Gao,2 Mingxia Wang,2 Ziqiang Tian1 1Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Ziqiang Tian, Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei, 050011, People’s Republic of China, Email [email protected] Mingxia Wang, Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, 050011, People’s Republic of China, Email [email protected]: 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 C18 column (100× 2.1 mm, 2.6 μm).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 AUC0-t, AUC0-∞, Cmax, Vz/F and t1/2 in the simvastatin group showed no statistical differences among pharmacokinetic parameters (P> 0.05). However, the values of AUC0-t, AUC0-∞ and Cmax, 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.Keywords: erlotinib, simvastatin, itraconazole, drug–drug interaction, UPLC-MS/MS, pharmacokinetic
