Premium
Pharmacokinetic basis for dosing high‐dose methotrexate in infants and young children with malignant brain tumours
Author(s) -
Panetta John C.,
Roberts Jessica K.,
Huang Jie,
Lin Tong,
Daryani Vinay M.,
Harstead K. Elaine,
Patel Yogesh T.,
OnarThomas Arzu,
Campagne Olivia,
Ward Deborah A.,
Broniscer Alberto,
Robinson Giles,
Gajjar Amar,
Stewart Clinton F.
Publication year - 2020
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14160
Subject(s) - medicine , pharmacokinetics , dosing , population , methotrexate , body surface area , volume of distribution , therapeutic drug monitoring , concomitant , dose , incidence (geometry) , pharmacology , pediatrics , environmental health , physics , optics
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/m 2 or 2.5 g/m 2 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/m 2 and 14.4 L/m 2 , 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.