Vincristine dosing, drug exposure and therapeutic drug monitoring in neonate and infant cancer patients. (March 2022)

• Record Type: Journal Article
• Authors: Barnett, Shelby; Hellmann, Farina; Parke, Elizabeth; Makin, Guy; Tweddle, Deborah A.; Osborne, Caroline; Hempel, Georg; Veal, Gareth J.
• Is Part Of: European journal of cancer. Volume 164(2022)
• Page Start: 127
• Page End: 136
• Publication Date: 2022-03
• Subjects: Vincristine -- Chemotherapy -- Pharmacokinetics -- Dosing -- Paediatrics -- Neonates -- Infants -- Therapeutic drug monitoring; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.09.014
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: 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 challenging 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 pharmacokinetic 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 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. Conclusion: Doses 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: Vincristine dosing and drug exposure was investigated in neonates and infants. Vincristine concentrations were quantified in 210 plasma samples from 57 children. Lower drug exposures were observed in infants and neonates compared with older children. Therapeutic drug monitoring can be used to avoid suboptimal vincristine drug exposures. Vincristine dosing guidance is provided for treatment of neonate and infant patients.