Bohn Jan-Paul, Reinstadler Vera, Pall Georg, Stockhammer Günther, Steurer Michael, Oberacher Herbert, Wolf Dominik
Department of Internal Medicine V, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, Innsbruck, Austria.
Eur J Drug Metab Pharmacokinet. 2019 Dec;44(6):845-851. doi: 10.1007/s13318-019-00572-w.
Liposomal cytarabine is a slow-release formulation for intrathecal application in patients with neoplastic meningitis. Although standard dosing intervals range from 2 to 4 weeks, it is unclear whether sustained cytotoxic cerebrospinal fluid (CSF) concentrations can be achieved beyond 14 days from drug injection. The objective of this study was to assess CSF and plasma concentrations of liposomal cytarabine more than 2 weeks after lumbar drug administration and to correlate those findings with clinical outcome.
66 matched CSF and plasma drug concentrations were analyzed by a validated liquid chromatography-tandem mass spectrometry method starting at day 13 from lumbar drug injection in 19 patients with neoplastic meningitis treated with liposomal cytarabine. CSF drug concentrations were correlated with clinical outcome.
Overall response rate was 63.2% (12/19). 100% (9/9) of patients with positive CSF cytology at diagnosis achieved cytological complete remission, and none of the patients (0/19) experienced on-drug disease progression. In responding patients with controlled systemic disease, CNS-specific progression-free survival was 14 months (n = 4; range 5-25 months). The median CSF concentration of free cytarabine was 156 ng/ml (range 5-4581 ng/ml) and 146 ng/ml (range 5-353 ng/ml) in samples withdrawn at days 13-16 and at days 25-29 after intrathecal drug injection, respectively. Free cytarabine concentrations > 100 ng/ml were detected in 58.8% (20/34) and 53.3% (7/13) of the CSF samples obtained at days 13-16 and days 25-29, respectively. CSF drug concentrations did not differ significantly between responding and nonresponding patients.
Liposomal cytarabine permits prolonged CSF drug exposure, with cytotoxic cytarabine concentrations that are detectable for 4 weeks in the majority of patients. The preserved clinical activity seen in patients with inferior CSF drug concentrations (< 100 ng/ml) suggests that maintaining lower cytarabine concentrations for a longer period of time may be similarly effective as using short peak concentrations.
脂质体阿糖胞苷是一种用于肿瘤性脑膜炎患者鞘内给药的缓释制剂。尽管标准给药间隔为2至4周，但尚不清楚在药物注射14天后是否能实现脑脊液（CSF）中持续的细胞毒性浓度。本研究的目的是评估鞘内给药2周以上后脂质体阿糖胞苷在脑脊液和血浆中的浓度，并将这些结果与临床结局相关联。
采用经过验证的液相色谱 - 串联质谱法分析了19例接受脂质体阿糖胞苷治疗的肿瘤性脑膜炎患者从鞘内药物注射第13天开始的66对匹配的脑脊液和血浆药物浓度。脑脊液药物浓度与临床结局相关联。
总体缓解率为63.2%（12/19）。诊断时脑脊液细胞学检查阳性的患者中有100%（9/9）实现了细胞学完全缓解，且无一例患者（0/19）在用药期间出现疾病进展。在全身疾病得到控制的缓解患者中，中枢神经系统特异性无进展生存期为14个月（n = 4；范围5 - 25个月）。鞘内药物注射后第13 - 16天和第25 - 29天采集的样本中，游离阿糖胞苷的脑脊液中位浓度分别为156 ng/ml（范围5 - 4581 ng/ml）和146 ng/ml（范围5 - 353 ng/ml）。在第13 - 16天和第25 - 29天获得的脑脊液样本中，分别有58.8%（20/34）和53.3%（7/13）检测到游离阿糖胞苷浓度>100 ng/ml。缓解患者和未缓解患者的脑脊液药物浓度无显著差异。
脂质体阿糖胞苷可使脑脊液药物暴露时间延长，大多数患者在4周内可检测到具有细胞毒性的阿糖胞苷浓度。在脑脊液药物浓度较低（<100 ng/ml）的患者中观察到的临床活性得以保留，这表明较长时间维持较低的阿糖胞苷浓度可能与使用短时间的峰值浓度同样有效。
