METHODS: A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections.
RESULTS: Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens.
CONCLUSIONS: In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.
方法:开发并验证了一种稳定的同位素稀释液相色谱-串联质谱方法,用于测定和定量人血浆和血清中的midostaurin。在阿糖胞苷诱导化疗期间,分析了12例FMS样酪氨酸激酶3(FLT3)突变的AML患者的Midostaurin血清浓度,柔红霉素,还有Midostaurin.泊沙康唑用于预防侵袭性真菌感染。
结果:在0.01-8.00mg/L的浓度范围内证明了midostaurin的线性定量。所提出方法的日内和日内不精确度均在±10%以内。在诱导化疗的第一和第二周期中,分别采集了9例和3例患者的静脉血样。在37个独立的血清标本中确定,中位(范围)midostaurin血清浓度为7.9mg/L(1.5-26.1mg/L)。
结论:在一个真实的AML患者队列中,Midostaurin血清浓度的个体间变异性很高,强调与AML患者的最佳药物剂量有关的问题。个性化的剂量方法可以最大限度地提高midostaurin的安全性。需要前瞻性研究和分析方法的标准化以支持这种方法。