Dataset Information

Pharmacokinetic basis for dosing high-dose methotrexate in infants and young children with malignant brain tumours.

ABSTRACT:

Aims

No population pharmacokinetic studies of high-dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing.

Methods

Patients received 4 monthly courses of HDMTX (5 g/m² or 2.5 g/m² for infants aged ?31 days) as a 24-h infusion. Serial samples were analysed for MTX by an enzyme immunoassay method. Pharmacokinetic parameters were estimated using nonlinear mixed effects population modelling. Demographics, concomitant medications and genetic polymorphisms were considered as pharmacokinetic covariates while MTX exposure and patient age were considered as covariates for Grade 3 and 4 toxicities.

Results

The population pharmacokinetics of HDMTX were estimated in 178 patients (age range 0.02-4.7 years) in 648 courses. The population clearance and volume were 90 mL/min/m² and 14.4 L/m² , respectively. Significant covariates on body surface area adjusted MTX clearance included estimated glomerular filtration rate and co-treatment with dexamethasone or vancomycin. No significant association was observed between MTX toxicity and MTX exposure, patient age, leucovorin dosage or duration. MTX clearance in infants ?31 days at enrolment was 44% lower than in older infants, but their incidence of toxicity was not higher since they also received a lower MTX dosage.

Conclusions

By aggressively following institutional clinical guidelines, HDMTX-related toxicities were low, and using covariates from the population pharmacokinetic model enabled the calculation of a rational dosage for this patient population for future clinical trials.

SUBMITTER: Panetta JC

PROVIDER: S-EPMC7015755 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetic basis for dosing high-dose methotrexate in infants and young children with malignant brain tumours.

Panetta John C JC Roberts Jessica K JK Huang Jie J Lin Tong T Daryani Vinay M VM Harstead K Elaine KE Patel Yogesh T YT Onar-Thomas Arzu A Campagne Olivia O Ward Deborah A DA Broniscer Alberto A Robinson Giles G Gajjar Amar A Stewart Clinton F CF

British journal of clinical pharmacology 20200108 2

<h4>Aims</h4>No population pharmacokinetic studies of high-dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing.<h4>Methods</h4>Patients received 4 monthly courses of HDMTX (5 g/m<sup>2</sup> or 2.5 g/m<sup>2</sup> for infants aged ≤31 days) as a 24-h infusion. Serial samples were analysed for MTX by an enzyme immunoassay ...[more]

PMID: 31657864

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Dataset Information

Pharmacokinetic basis for dosing high-dose methotrexate in infants and young children with malignant brain tumours.

Aims

Methods

Results

Conclusions

Publications

Pharmacokinetic basis for dosing high-dose methotrexate in infants and young children with malignant brain tumours.

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