Abstract：
OBJECTIVE: Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors.
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.
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.
摘要：
目的：Midostaurin是一种口服多靶向酪氨酸激酶抑制剂，用于治疗急性髓系白血病（AML）。当怀疑毒性或与强CYP3A4抑制剂联合使用时，midostaurin的治疗药物监测可能支持其安全使用。
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。
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。
