The Population Pharmacokinetics of High-Dose Methotrexate in Infants with Acute Lymphoblastic Leukemia Highlight the Need for Bedside Individualized Dose Adjustment: A Report from the Children’s Oncology Group

Abstract

Background: Infants with acute lymphoblastic leukemia (ALL) treated with high-dose methotrexate (MTX) may have reduced MTX clearance (CL) due to renal immaturity, which may predispose them to toxicity. The objective of this study was to develop a population pharmacokinetic (PK) model of MTX in infants with ALL.Methods: A total of 672 MTX plasma concentrations were obtained from 71 infants enrolled in the Children's Oncology Group (COG) Clinical Trial P9407. Infants received MTX 4 g/m 2 intravenously for four cycles during weeks 4-12 of intensification. A population PK analysis was performed using NONMEM® version 7.4. The final model was evaluated using a non-parametric bootstrap, a visual predictive check, and simulations were performed to evaluate MTX dosage and the utility of a bedside algorithm for dose individualization.Results: MTX was best characterized by a two-compartment model with allometric scaling. Weight was the only covariate included in the final model. The coefficient of variation for interoccasion variability (IOV) on CL was relatively high at 25.4%, compared to the

MTXPK.org: A Clinical Decision Support Tool Evaluating High‐Dose Methotrexate Pharmacokinetics to Inform Post‐Infusion Care and Use of Glucarpidase

“…Typical MTX population PK models are developed using PK data up to 44 hours after the start of infusion [18][19][20][21][22][23] or contain few samples from patients with delayed MTX clearance. 28,34,35 These models overestimate MTX clearance and plasma concentrations when used to evaluate patients with delayed MTX clearance (as illustrated by the NOPHO two-compartment model in Figure 2b). The three-compartment model provides a better estimation of the average elimination profile for the population and improved the description of the significant interpatient variability compared with the two-compartment model, which are critical for the accurate visualization and appropriate interpretation of the glucarpidase drug label.…”

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

“…However, data describing MTX pharmacokinetics in infants remain limited. Only 1 population pharmacokinetic study including infants <6 months has been published, but it was in patients with acute lymphoblastic leukaemia, had a small patient population of infants only ( n = 17), and had limited covariates (weight, age, body surface area and sex) . Other pharmacokinetic studies in infants have been published but often with contradictory pharmacokinetic results .…”

“…Only 1 population pharmacokinetic study including infants <6 months has been published, but it was in patients with acute lymphoblastic leukaemia, had a small patient population of infants only (n = 17), and had limited covariates (weight, age, body surface area and sex). 11 Other pharmacokinetic studies in infants have been published but often with contradictory pharmacokinetic results. 12,13 These limited evaluations have been inadequate, suffering from small numbers of infants, and heterogeneous enrolment criteria and treatment strategies.…”

Clinical pharmacokinetics of methotrexate in the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma in pediatric patients

“…Značajni su rezultati novije metodologije bazirane na populacionoj farmakokinetičkoj analizi. U studiji u pedijatrijskim pacijentima sa ALL (2,9-12,9 meseci) zabeležena je vrednost CL od 11,0 L/h/70kg, skalirana na standardnu telesnu masu od 70 kg, omogućavajući autorima da uporede rezultat sa odraslim ispitanicima i ukažu na moguću sličnost (29). Prema rezultatima analize na pacijentima sa širim opsegom godina (1-18), tipična vrednost CL je bila 6,68 L/h/m 2 (30).…”

“…Pored navedenog, u prethodnim studijama su razmatrani i pol, enzimi jetre, ali i spoljašnji faktori kao interakcije lekova (16). Što se tiče populacionih studija u pedijatrijskoj populaciji, opisan je uticaj pre svega serumskog kreatinina na CL (1-18 godina sa ALL) (30), zatim telesne mase na farmakokinetičke parametre (29,35), ali i godina na vrednost CL (31). Ipak, ograničen broj populacionih studija na deci koji opisuju uticaj svih relevantnih faktora varijabilnosti i često mali broj ispitanika, nameće potrebu za daljim istraživanjima, radi bolje optimizacije terapije MTX i procene doze leukovorina kod individualnog pacijenta.…”