Effects of voriconazole and fluconazole on the pharmacokinetics of almonertinib in rats by UPLC–MS/MS

Abstract

Almonertinib was included in the first‐line treatment of non‐small cell lung cancer with EGFR T790M mutations by the Chinese Society of Clinical Oncology in 2021. Considering that immunocompromised lung cancer patients are prone to opportunistic fungal infections, and most triazole antifungal drugs are moderate or strong inhibitors of CYP3A4, this study was conducted to develop and validate an accurate and rapid ultra‐performance liquid chromatography tandem mass spectrometry method for quantifying almonertinib in plasma and for investigating the pharmacokinetic changes of almonertinib caused by voriconazole and fluconazole in rats. After liquid–liquid extraction with tert‐butyl methyl ether, an XSelect HSS T3 column (2.1 × 100 mm, 2.5 μm, Waters) was used for the chromatographic separation of almonertinib and sorafenib‐D3 (internal standard). The analytes were detected using an AB Sciex Triple Quad 5,500 mass spectrometer in the positive ionization mode. The method exhibited great linearity (0.5–200 ng/ml, r > 0.997) and stability under the established experimental conditions. All validation experiments were in accordance with the guidelines, and the results were all within the acceptable limits. This method was successfully applied to the researches of pharmacokinetics and drug interactions for almonertinib in rats. Voriconazole and fluconazole significantly altered the pharmacokinetic profiles of almonertinib and increased the systemic exposure of almonertinib in rats to different degrees, but further human trials should be conducted to validate the results.

The influence of drug-induced metabolic enzyme activity inhibition and CYP3A4 gene polymorphism on aumolertinib metabolism

“…It has been reported that CYP3A4 is the main enzyme system responsible for catalyzing the generation of HAS-719 from aumolertinib. Due to its rich genetic polymorphism and susceptibility to drug induction or inhibition, changes in CYP3A4 enzyme activity can lead to fluctuations in aumolertinib blood exposure and affect efficacy (Zhou, 2008;Fu et al, 2023). Although other factors, such as food, gender, age, and more, can also influence the pharmacokinetic characteristics of drug metabolism, these aspects were not the focus or within the scope of the present study (Hoover et al, 2016).…”

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

“…Xun et al revealed that VCZ inhibited the metabolism of atorvastatin, and had a significant interaction with atorvastatin in patients with fungal infections and dyslipidemia ( Xun et al, 2023 ). A recent study demonstrated that VCZ and FCZ increased the systemic exposure of almonertinib by 2.7-fold and 3.4-fold, respectively ( Fu et al, 2023 ). Midazolam is regularly utilized as a probe substrate to assess CYP3A activity, and the AUC 0–360 of midazolam was significantly increased (133%) ( U.S. Food and Drug Administration, 2017 ; European Medicines Agency, 2012 ; Uchida, Tanaka & Namiki, 2014 ).…”

Evaluation of the inhibitory effect of azoles on pharmacokinetics of lenvatinib in rats both in vivo and in vitro by UPLC‐MS/MS

“…The validation process encompassed the assessment of various parameters, such as selectivity, calibration curve, lower line of quantification (LLOQ), accuracy, precision, matrix effect, recovery and stability. 21…”

“…This study was validated conducted in accordance with the bioanalytical method validation principles established by FDA. The validation process encompassed the assessment of various parameters, such as selectivity, calibration curve, lower line of quantification (LLOQ), accuracy, precision, matrix effect, recovery and stability 21 …”