Vincristine dosing, drug exposure and therapeutic drug monitoring in neonate and infant cancer patients

Background: The anticancer drug vincristine is associated with potentially dose-limiting side-effects, including neurotoxicity and myelosuppression. However, there currently exists a lack of published clinical pharmacology data relating to its use in neonate and infant patients. We report a study investigating vincristine dosing and drug exposure, alongside the feasibility and impact of a therapeutic drug monitoring treatment approach, in this chal-lenging patient population. Patients and methods: Vincristine pharmacokinetic data from a total of 57 childhood cancer patients, including 26 neonates and infants, were used to characterise a population pharmaco-kinetic model. Vincristine was administered at doses of 0.02-0.05 mg/kg or 0.75-1.5 mg/m(2) in neonates and infants aged < 1 year or <= 12 kg and doses of 1.5 mg/m(2) in older children. Results: A two-compartment model provided the best fit for the population analysis. There was no significant difference in vincristine clearance normalised for body surface area between neonates/infants and older children. Lower doses administered to neonates and infants re-sulted in significantly lower drug exposures (area under the curve [AUC]), compared with old -er children (p =0.047). Vincristine doses of < 0.05 mg/kg in neonates and infants resulted in significantly lower AUC values than observed in those receiving doses of >= 0.05 mg/kg (p <= 0.0001). Therapeutic drug monitoring was shown to be feasible, effective and well toler-ated in neonates and infants experiencing suboptimal drug exposures. Conclusion:Doses of < 0.05 mg/kg should not be used in neonate and infant patients becauseof a high risk of patients experiencing potentially suboptimal drug exposures. Therapeuticdrug monitoring approaches in neonates and infants are supported by the data generated, witha proposed target therapeutic window of 50e100mg/l*h. (C) 2021 The Authors. Published by Elsevier Ltd