Population pharmacokinetics and dose-response relationships of mitoxantrone in children with acute myeloid leukaemia.
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BACKGROUND: Information on mitoxantrone pharmacokinetics in children is lacking and reduced dosing regimens applied to infants are supported by limited scientific rationale. The current study characterized mitoxantrone pharmacokinetics in a childhood acute myeloid leukaemia patient population and provides a data-informed assessment of dosing. METHODS: A total of 282 plasma samples from 44 patients aged 0.9-17 years, receiving intravenous mitoxantrone at doses of 12 mg/m2/day or 0.4 mg/kg/day (patients <12 months, ≤10 kg or <0.5 m2), were analysed, and a population pharmacokinetic model was developed. Individual clearance (CL) values were used to calculate mitoxantrone area under the plasma concentration-time curve (AUC) for each patient. Relationships among dosing regimen, pharmacokinetics and toxicity were assessed. Simulation of 1000 virtual patients, sampled from real covariate combinations, was used to investigate standardized patient dosing. RESULTS: A two-compartment model with fixed allometric scaling best described the data, with a final population estimated CL of 39.1 L/h (residual standard error 9.6%) observed for a patient weighing 27.5 kg. Infants receiving mg/kg dosing exhibited lower AUC values (192 ± 75 μg·h/L) than the mg/m2 group (317 ± 184 μg·h/L). Simulations showed that a standardized 12 mg/m2/day dosing regimen would likely result in comparable AUCs across all ages. No correlation was observed between mitoxantrone AUC and incidence of severe toxicity (Common Terminology Criteria for Adverse Events [CTCAE] grade 3/4) in this cohort. CONCLUSION: This study provides novel insights into the pharmacokinetics of mitoxantrone in children. Infant patients receiving body weight-based dosing regimens may be at risk of suboptimal drug exposure, and many of these patients may tolerate higher mitoxantrone doses in line with older children. This trial was registered with the EU Clinical Trials Register (EudraCT number 2014-005066-30).