Verheijen Remy B, Thijssen Bas, Rosing Hilde, Schellens Jan H M, Nan Lianda, Venekamp Nikkie, Beijnen Jos H, Steeghs Neeltje, Huitema Alwin D R
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek.
Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam.
Ther Drug Monit. 2018 Apr;40(2):230-236. doi: 10.1097/FTD.0000000000000479.
Pazopanib is an angiogenesis inhibitor approved for renal cell carcinoma and soft-tissue sarcoma. Studies indicate that treatment with pazopanib could be optimized by adapting the dose based on measured pazopanib plasma concentrations.
We describe the validation and clinical application of a fast and straightforward method for the quantification of pazopanib in human plasma for the purpose of therapeutic drug monitoring and bioanalytical support of clinical trials. Stable isotopically labeled C,H3-pazopanib was used as internal standard. Plasma samples were prepared for analysis by protein precipitation using methanol and diluted with 10 mmol/L ammonium hydroxide buffer. Chromatographic separation was performed on a C18 column using isocratic elution with ammonium hydroxide in water and methanol. For detection, a tandem mass spectrometer, equipped with a turbo ion spray interface was used in positive ion mode at m/z 438 → m/z 357 for pazopanib and m/z 442 → m/z 361 for the internal standard.
Final runtime was 2.5 minutes. All validated parameters were within pre-established limits and fulfilled the FDA and EMA requirements for bioanalytical method validation. After completion of the validation, the routine application of the method was tested by analyzing clinical study samples that were collected for the purpose of therapeutic drug monitoring.
In conclusion, the described method was successfully validated and was found to be robust for routine application to analyze samples from cancer patients treated with pazopanib.
帕唑帕尼是一种被批准用于治疗肾细胞癌和软组织肉瘤的血管生成抑制剂。研究表明，基于所测得的帕唑帕尼血浆浓度调整剂量，可优化帕唑帕尼治疗方案。
我们描述了一种快速简便的人血浆中帕唑帕尼定量方法的验证及临床应用，用于治疗药物监测及临床试验的生物分析支持。稳定同位素标记的C,H3-帕唑帕尼用作内标。血浆样本通过甲醇蛋白沉淀法制备用于分析，并用10 mmol/L氢氧化铵缓冲液稀释。在C18柱上进行色谱分离，采用水和甲醇中含氢氧化铵的等度洗脱。检测时，使用配备涡轮离子喷雾接口的串联质谱仪，在正离子模式下，帕唑帕尼的m/z为438 → m/z 357，内标的m/z为442 → m/z 361。
最终运行时间为2.5分钟。所有验证参数均在预先设定的范围内，满足FDA和EMA对生物分析方法验证的要求。验证完成后，通过分析为治疗药物监测而收集的临床研究样本，对该方法的常规应用进行了测试。
总之，所描述的方法成功验证，且发现其在常规应用中对于分析接受帕唑帕尼治疗的癌症患者样本具有稳健性。
