Niu Xiaochen, Chen Dan, He Wei, Tang Yu, Zhao Jianchun
School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Marine Biomedical Research Institute of Qingdao, Qingdao 266073, China.
Pharmaceuticals (Basel). 2023 Aug 14;16(8):1153. doi: 10.3390/ph16081153.
Plinabulin, a new antitumor drug developed from marine natural products that targets microtubules in cancer cells, is currently being tested in a phase III clinical study. Plinabulin has been clinically proven to be effective on leukopenia. However, to our knowledge, there are no reports investigating the pharmacokinetics of plinabulin in individuals with leukopenia and healthy individuals. In this study, we developed a rapid and sensitive UHPLC-MS/MS method for the detection of plinabulin for the first time. Using a novel cyclophosphamide-induced leukopenia model, we investigated the differences in the pharmacokinetic characteristics of plinabulin between rats with leukopenia and normal rats. Plinabulin and propranolol (IS) peaks were separated by gradient elution for a total run time of 5 min. The methodological validation showed a good accuracy (101.96-109.42%) and precision (RSD ≤ 5.37%) with the lower limit of quantification at 0.5 ng/mL. The recovery of plinabulin was between 91.99% and 109.75% (RSD ≤ 7.92%). The values of the area under the plasma concentration-time curve (AUC) for leukopenia groups and control groups at doses of 0.5 mg/kg, 1 mg/kg, and 3 mg/kg were 148.89 ± 78.74 h·μg/L and 121.75 ± 31.56 h·μg/L; 318.15 ± 40.00 h·μg/L and 272.06 ± 42.85 h·μg/L; and 1432.43 ± 197.47 h·μg/L and 1337.12 ± 193.56 h·μg/L; respectively. The half-lives (ts) of plinabulin were 0.49-0.72 h for leukopenia groups and 0.39-0.70 h for control groups at three doses, and the clearance rates (CLs) of plinabulin were 2.13-3.87 L/h/kg for leukopenia groups and 2.29-4.23 L/h/kg for control groups. Pharmacokinetic results showed that there was no significant pharmacokinetic difference between the normal group and the leukopenia group. Based on the power model, plinabulin exhibits a lack of dose proportionality over the dose range of 0.5-3 mg/kg after intravenous administration. This study provides guidance for the development of plinabulin as a potential candidate for the treatment of chemotherapy-induced leukopenia.
普利纳布林是一种从海洋天然产物中开发的新型抗肿瘤药物，其作用靶点为癌细胞中的微管，目前正在进行III期临床研究。普利纳布林已在临床上被证明对白细胞减少有效。然而，据我们所知，尚无关于普利纳布林在白细胞减少个体和健康个体中的药代动力学研究报告。在本研究中，我们首次开发了一种快速灵敏的超高效液相色谱-串联质谱法（UHPLC-MS/MS）用于检测普利纳布林。使用新型环磷酰胺诱导的白细胞减少模型，我们研究了白细胞减少大鼠和正常大鼠之间普利纳布林药代动力学特征的差异。通过梯度洗脱分离普利纳布林和普萘洛尔（内标，IS）峰，总运行时间为5分钟。方法学验证显示准确度良好（101.96 - 109.42%）和精密度良好（相对标准偏差≤5.37%），定量下限为0.5 ng/mL。普利纳布林的回收率在91.99%至109.75%之间（相对标准偏差≤7.92%）。白细胞减少组和对照组在0.5 mg/kg、1 mg/kg和3 mg/kg剂量下的血浆浓度-时间曲线下面积（AUC）值分别为148.89±78.74 h·μg/L和121.75±31.56 h·μg/L；318.15±40.00 h·μg/L和272.06±42.85 h·μg/L；以及1432.43±197.47 h·μg/L和1337.12±193.56 h·μg/L。在三个剂量下，白细胞减少组普利纳布林的半衰期（t1/2）为0.49 - 0.72小时，对照组为0.39 - 0.70小时，白细胞减少组普利纳布林的清除率（CL）为2.13 - 3.87 L/h/kg，对照组为2.29 - 4.23 L/h/kg。药代动力学结果表明正常组和白细胞减少组之间没有显著的药代动力学差异。基于幂模型，静脉给药后，在0.5 - 3 mg/kg剂量范围内，普利纳布林表现出剂量不成比例性。本研究为普利纳布林作为化疗诱导白细胞减少治疗的潜在候选药物的开发提供了指导。
