title: Pharmacokinetics and toxicity of intrathecal liposomal cytarabine in children and adolescents following age-adapted dosing.
abstract: OBJECTIVE
  Assessment of the optimal drug dose for intrathecal therapy in children is challenging because of the non-linear increase in cerebrospinal fluid (CSF) volume throughout childhood and potential differences in the elimination rate in children versus adults. The present study was designed to prospectively collect pharmacokinetic and safety data on age-adapted intrathecal liposomal cytarabine in children aged >3 years.
  
  
  METHODS
  Sixteen patients with malignant brain tumours were included in the study. Children aged 3-10 years received liposomal cytarabine 35 mg with concomitant dexamethasone, and those aged >10 years received 50 mg. Serial CSF and plasma samples were collected before administration and 1 h, 12 h, 24 h, 1 week and 2 weeks post-dosing. CSF was analysed for free and encapsulated cytarabine, and plasma was analysed for free cytarabine.
  
  
  RESULTS
  The average elimination half-life values in children aged 3-10 years and in those aged >10 years, treated with liposomal cytarabine 35 mg and 50 mg, respectively, were 40.9 and 43.7 h for free cytarabine and 31.5 and 36.4 h for encapsulated cytarabine in CSF. Although these values were lower than those previously reported, cytarabine concentrations exceeded the cytotoxic threshold of 0.1 mg/L in all patients until 1 week post-intraventricular administration. Cytarabine concentrations in plasma were negligible. In general, liposomal cytarabine was well tolerated, with relevant but manageable toxicities.
  
  
  CONCLUSIONS
  Liposomal cytarabine in doses of 35 mg for children aged 3-10 years and 50 mg for older patients shows sufficient drug exposure for at least 1 week and appears to be well tolerated.
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peyrl
authors.forename: Robert
authors.initials: R
authors.lastname: Sauermann
authors.forename: Monika
authors.initials: M
authors.lastname: Chocholous
authors.forename: Amedeo A
authors.initials: AA
authors.lastname: Azizi
authors.forename: Walter
authors.initials: W
authors.lastname: Jäger
authors.forename: Martina
authors.initials: M
authors.lastname: Höferl
authors.forename: Irene
authors.initials: I
authors.lastname: Slavc
mesh_terms: D000293:Adolescent; D000375:Aging / Q000502:physiology; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008081:Liposomes; D008297:Male
chemical_list: D000964:Antimetabolites, Antineoplastic; D008081:Liposomes; D003561:Cytarabine