Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, China.
J Pharm Biomed Anal. 2023 Apr 1;227:115279. doi: 10.1016/j.jpba.2023.115279. Epub 2023 Feb 1.
Venetoclax, an orally bioavailable BCL-2 inhibitor, has been regarded as a breakthrough for the treatment of leukemia but has a wide interindividual variability and drug-drug interaction in pharmacokinetics. In this study, a simple and sensitive ultra-high performance liquid chromatography-tandem with mass spectrometry method was established and fully validated to quantify venetoclax and voriconazole simultaneously in human plasma. After protein precipitation, the analytes were separated on a Hypersil GOLD C18 column (3 µm, 2.1 × 50 mm) by gradient elution. The mass detection was operated under multiple reaction monitoring mode at m/z 868.5 →636.2 for venetoclax, 350.0 → 127.0 for voriconazole and 353.0 → 127.0 for voriconazole-D3(Internal Standard). The calibration ranges were 0.1-10 μg/mL for venetoclax and 0.05-10 μg/mL for voriconazole with correlation coefficients (r)＞0.998. The validated method was successfully applied to the pharmacokinetic study in acute myeloid leukemia patients receiving venetoclax with or without voriconazole. The results suggested that co-treatment with 200 mg q12h voriconazole, the peak concentration of venetoclax (100 mg qd) could be raised to the same level as the 400 mg qd group. However, the trough concentration of venetoclax (100 mg qd) was much higher than that of the 400 mg qd group. Therapeutic drug monitoring might give some guidance for the adjustment of dosing regimens to guarantee the drug efficacy and safety of patients to some extent.
维奈托克是一种口服生物可利用的 BCL-2 抑制剂，被认为是治疗白血病的突破，但在药代动力学方面具有广泛的个体间变异性和药物相互作用。在这项研究中，建立了一种简单灵敏的超高效液相色谱-串联质谱法，并用其定量检测人血浆中的维奈托克和伏立康唑。经过蛋白沉淀后，在 Hypersil GOLD C18 柱（3μm，2.1×50mm）上进行梯度洗脱分离。在多反应监测模式下，以 m/z 868.5→636.2 检测维奈托克，以 m/z 350.0→127.0 检测伏立康唑，以 m/z 353.0→127.0 检测伏立康唑-D3（内标）。维奈托克的校准范围为 0.1-10μg/mL，伏立康唑的校准范围为 0.05-10μg/mL，相关系数（r）均＞0.998。该方法已成功应用于接受维奈托克联合或不联合伏立康唑治疗的急性髓系白血病患者的药代动力学研究。结果表明，与伏立康唑（200mg q12h）联用时，维奈托克（100mg qd）的峰浓度可提高至与 400mg qd 组相同水平。然而，维奈托克（100mg qd）的谷浓度远高于 400mg qd 组。治疗药物监测在一定程度上可能有助于调整给药方案，以保证患者的药物疗效和安全性。
