Pharmacokinetics and Toxicity of Intrathecal Liposomal Cytarabine in Children and Adolescents Following Age-Adapted Dosing

Abstract

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 >3years. Sixteen patients with malignant brain tumours were included in the study. Children aged 3-10years received liposomal cytarabine 35mg with concomitant dexamethasone, and those aged >10years received 50mg. Serial CSF and plasma samples were collected before administration and 1h, 12h, 24h, 1week and 2weeks post-dosing. CSF was analysed for free and encapsulated cytarabine, and plasma was analysed for free cytarabine. The average elimination half-life values in children aged 3-10years and in those aged >10years, treated with liposomal cytarabine 35mg and 50mg, respectively, were 40.9 and 43.7h for free cytarabine and 31.5 and 36.4h for encapsulated cytarabine in CSF. Although these values were lower than those previously reported, cytarabine concentrations exceeded the cytotoxic threshold of 0.1mg/L in all patients until 1week post-intraventricular administration. Cytarabine concentrations in plasma were negligible. In general, liposomal cytarabine was well tolerated, with relevant but manageable toxicities. Liposomal cytarabine in doses of 35mg for children aged 3-10years and 50mg for older patients shows sufficient drug exposure for at least 1week and appears to be well tolerated.