Pharmacokinetic basis for dosing high-dose methotrexate in infants and young children with malignant brain tumours.
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.
['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|0000-0002-1546-9720']
D000368:Aged D000964:Antimetabolites, Antineoplastic D001932:Brain Neoplasms D002648:Child D002675:Child, Preschool D064420:Drug-Related Side Effects and Adverse Reactions D006801:Humans D007223:Infant D007231:Infant, Newborn D002955:Leucovorin D008727:Methotrexate
anticancer drugs<oncology children<paediatrics pharmacokinetics-pharmacodynamics<pharmacodynamics population analysis<pharmacodynamics