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.
Highlights
Similar to many well-established anticancer drugs, the use of the tubulin-binding agent vincristine is associated with potentially dose-limiting side-effects, including neurotoxicity and myelosuppression [1,2]
Doses of
Therapeutic drug monitoring approaches in neonates and infants are supported by the data generated, with a proposed target therapeutic window of 50e100 mg/l*h. a 2021 The Authors
Summary
Similar to many well-established anticancer drugs, the use of the tubulin-binding agent vincristine is associated with potentially dose-limiting side-effects, including neurotoxicity and myelosuppression [1,2]. It is imperative that dosing regimens used provide the best chance of eliciting a clinical response, it is important to consider the potential short- and long-term effects of treatment in a clearly vulnerable patient population. This is important for a drug such as vincristine, which is widely used across a range of paediatric malignancies, including leukaemias, lymphomas, sarcomas, brain tumours and neuroblastoma [4,5]. Therapeutic drug monitoring was shown to be feasible, effective and well tolerated in neonates and infants experiencing suboptimal drug exposures
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