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

Abstract

BackgroundThe 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 challenging patient population. Patients and methodsVincristine pharmacokinetic data from a total of 57 childhood cancer patients, including 26 neonates and infants, were used to characterise a population pharmacokinetic model. Vincristine was administered at doses of 0.02–0.05 mg/kg or 0.75–1.5 mg/m2 in neonates and infants aged <1 year or ≤12 kg and doses of 1.5 mg/m2 in older children. ResultsA 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 resulted in significantly lower drug exposures (area under the curve [AUC]), compared with older 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 tolerated in neonates and infants experiencing suboptimal drug exposures. ConclusionDoses of <0.05 mg/kg should not be used in neonate and infant patients because of a high risk of patients experiencing potentially suboptimal drug exposures. Therapeutic drug monitoring approaches in neonates and infants are supported by the data generated, with a proposed target therapeutic window of 50–100 μg/l∗h.