Department of Pharmacy, Wenzhou People's Hospital, Wenzhou, Zhejiang 325000, People's Republic of China.
Department of Brain Surgery, The People's Hospital of Lishui, Lishui, Zhejiang 323000, People's Republic of China.
Drug Des Devel Ther. 2020 May 26;14:2061-2067. doi: 10.2147/DDDT.S243760. eCollection 2020.
Gilteritinib, a novel, potent FLT3/AXL inhibitor, was recently approved in Japan and USA for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation.
In this study, we aimed to develop and validate a sensitive and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantification of gilteritinib in plasma and to investigate whether CYP3A4 inhibitors (fluconazole and itraconazole) could influence the pharmacokinetics of gilteritinib from a drug-drug interaction study in rats. Sample preparation was done by a simple protein crash with acetonitrile containing the internal standard (IS) pirfenidone, followed by UPLC-MS/MS quantification.
The assay was successfully validated in a 1-500 ng/mL calibration range for gilteritinib, where the lower limit of quantification (LLOQ) was set at 1 ng/mL. The intra-day and inter-day precisions for gilteritinib were less than 10.6%, and the accuracies were in the range of -14.5% to 11.1%. Recovery and matrix effect of the analyte and IS were acceptable, and the analyte was stable during the assay and storage in plasma samples. The validated UPLC-MS/MS method was successfully applied to a drug-drug interaction study between gilteritinib and CYP3A4 inhibitors (fluconazole and itraconazole) in rats. Itraconazole significantly increased the exposure of gilteritinib, and affected the pharmacokinetics of gilteritinib in rats, not fluconazole.
A further clinical study should be conducted to investigate the effect of itraconazole on the metabolism of gilteritinib in subjects.
新型强效 FLT3/AXL 抑制剂吉特替尼最近在日本和美国获得批准，用于治疗伴有 FLT3 突变的复发/难治性急性髓系白血病（AML）成人患者。
本研究旨在开发和验证一种灵敏、简便的超高效液相色谱串联质谱（UPLC-MS/MS）法，用于检测血浆中的吉特替尼，并通过大鼠药物相互作用研究探讨 CYP3A4 抑制剂（氟康唑和伊曲康唑）是否会影响吉特替尼的药代动力学。样品制备采用简单的蛋白沉淀法，用含内标（吡非尼酮）的乙腈处理，然后进行 UPLC-MS/MS 定量分析。
该方法在 1-500ng/mL 的校准范围内成功验证，定量下限（LLOQ）设定为 1ng/mL。日内和日间精密度小于 10.6%，准确度在-14.5%至 11.1%范围内。分析物和内标的回收率和基质效应可接受，且分析物在检测和血浆样品储存过程中稳定。已验证的 UPLC-MS/MS 方法成功应用于大鼠中吉特替尼与 CYP3A4 抑制剂（氟康唑和伊曲康唑）之间的药物相互作用研究。伊曲康唑显著增加了吉特替尼的暴露量，并影响了吉特替尼在大鼠中的药代动力学，而氟康唑无此影响。
应进行进一步的临床研究，以调查伊曲康唑对受试者中吉特替尼代谢的影响。
