Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats

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 patients with cancer to reduce the risk of opportunistic fungal infections. In this study, we investigated whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could affect the pharmacokinetics of osimertinib in rats. We reported that when co-administered with voriconazole and fluconazole, the Cmax of osimertinib increased by 58.04% and 53.45%, respectively; the AUC0–t of osimertinib increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0–t of osimertinib increased by 13.91% and 34.80%, respectively. Our results revealed that voriconazole and fluconazole could significantly influence the pharmacokinetic profiles of osimertinib in rats, whereas the strong inhibitor CYP3A itraconazole did not; co-administration of osimertinib and voriconazole or fluconazole is not recommended in ongoing clinical practice.