Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats
Yutao Lou,
Feifeng Song,
Mengting Cheng,
Ying Hu,
Yitao Chai,
Qing Hu,
Qiyue Wang,
Hongying Zhou,
Meihua Bao,
Jinping Gu,
Yiwen Zhang
Affiliations
Yutao Lou
College of Pharmacy, Zhejiang University of Technology, Hanghzhou, Zhejiang, China
Feifeng Song
Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Mengting Cheng
Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Ying Hu
Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Yitao Chai
Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Qing Hu
Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Qiyue Wang
Clinical Pharmacy Center, Department of Pharmacy, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Hongying Zhou
Department of Oncology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
Meihua Bao
Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, China
Jinping Gu
College of Pharmacy, Zhejiang University of Technology, Hanghzhou, Zhejiang, China
Yiwen Zhang
College of Pharmacy, Zhejiang University of Technology, Hanghzhou, Zhejiang, China
Background Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats. Methods The adult male Sprague-Dawley rats were randomly divided into four groups (n = 6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0–48 h after osimertinib administration. Osimrtinib’s plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min. Results Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0–t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0–t of osimertinib only increased by 13.91% and 34.80%, respectively. Conclusions Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals.
