Peyrl Andreas, Sauermann Robert, Traunmueller Friederike, Azizi Amedeo A, Gruber-Olipitz Mariella, Gupper Astrid, Slavc Irene
Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
Clin Pharmacokinet. 2009;48(4):265-71. doi: 10.2165/00003088-200948040-00004.
Liposomal cytarabine (DepoCyte) is a slow-release formulation for intrathecal application, ensuring prolonged drug exposure. Although there is an urgent need for new treatment options for infants with leptomeningeal dissemination of a malignant brain tumour, there are no clinical and pharmacokinetic data available on this drug for children aged <3 years. The objective of this pilot study was to determine the feasibility, safety and pharmacokinetics of cytarabine after intrathecal administration of liposomal cytarabine 25 mg in patients aged <3 years.
Six male patients with a mean age of 21 months and CNS primitive neuroectodermal tumours (n = 3) or atypical teratoid/rhabdoid tumours (n = 3) were included. Liposomal cytarabine (25 mg) was administered intraventricularly. One patient also received the drug by lumbar puncture. Dexamethasone was used concomitantly for 3-5 days to prevent arachnoiditis. Cerebrospinal fluid (CSF) and plasma samples were collected before administration of liposomal cytarabine and 1 hour, 12 hours, 24 hours, 1 week and 2 weeks post-dosing. Noncompartmental pharmacokinetic analysis of CSF and plasma was performed.
Liposomal cytarabine was generally well tolerated; only grade 2 headache occurred in one patient. After intraventricular administration of cytarabine 25 mg, free and encapsulated drug concentrations above the cytotoxic drug level of 0.1 microg/mL were detectable in the CSF for at least 7 days and up to 14 days post-dosing. The average elimination half-lives were 56.7 hours for encapsulated cytarabine and 59.3 hours for free cytarabine. After intralumbar administration, the elimination half-life of free cytarabine, measured in the ventricular CSF during two courses in one patient, was significantly shorter (32.7 hours).
Application of liposomal cytarabine with concomitant dexamethasone appears to be safe and well tolerated in children aged <3 years. Drug exposure in infants aged <3 years after an intraventricular dose of 25 mg is comparable to that after administration of 50 mg in adult patients and 35 mg in older children.
脂质体阿糖胞苷（DepoCyte）是一种用于鞘内给药的缓释制剂，可确保药物长时间暴露。尽管对于患有恶性脑肿瘤软脑膜播散的婴儿迫切需要新的治疗选择，但尚无该药物用于3岁以下儿童的临床和药代动力学数据。这项初步研究的目的是确定在3岁以下患者鞘内注射25mg脂质体阿糖胞苷后阿糖胞苷的可行性、安全性和药代动力学情况。
纳入6名平均年龄为21个月的男性患者，其中3例患有中枢神经系统原始神经外胚层肿瘤，3例患有非典型畸胎样/横纹肌样肿瘤。脂质体阿糖胞苷（25mg）通过脑室内给药。1例患者还通过腰椎穿刺接受了该药物。同时使用地塞米松3 - 5天以预防蛛网膜炎。在给予脂质体阿糖胞苷前以及给药后1小时、12小时、24小时、1周和2周采集脑脊液（CSF）和血浆样本。对脑脊液和血浆进行非房室药代动力学分析。
脂质体阿糖胞苷总体耐受性良好；仅1例患者出现2级头痛。脑室内给予25mg阿糖胞苷后，给药后至少7天直至14天，脑脊液中可检测到游离和包裹药物浓度高于细胞毒性药物水平0.1μg/mL。包裹型阿糖胞苷平均消除半衰期为56.7小时，游离阿糖胞苷为59.3小时。腰椎穿刺给药后，在1例患者的两个疗程中，在脑室脑脊液中测得的游离阿糖胞苷消除半衰期明显较短（32.7小时）。
脂质体阿糖胞苷联合地塞米松应用于3岁以下儿童似乎安全且耐受性良好。3岁以下婴儿脑室内给予25mg剂量后的药物暴露情况与成年患者给予50mg以及大龄儿童给予35mg后的情况相当。
