title: Pharmacokinetics and safety of intrathecal liposomal cytarabine in children aged <3 years.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Paediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peyrl
authors.forename: Robert
authors.initials: R
authors.lastname: Sauermann
authors.forename: Friederike
authors.initials: F
authors.lastname: Traunmueller
authors.forename: Amedeo A
authors.initials: AA
authors.lastname: Azizi
authors.forename: Mariella
authors.initials: M
authors.lastname: Gruber-Olipitz
authors.forename: Astrid
authors.initials: A
authors.lastname: Gupper
authors.forename: Irene
authors.initials: I
authors.lastname: Slavc
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000188:drug therapy*; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D003907:Dexamethasone / Q000008:administration & dosage; D006261:Headache / Q000139:chemically induced*; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D010865:Pilot Projects
chemical_list: D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D003561:Cytarabine; D003907:Dexamethasone