Population pharmacokinetics of high‐dose methotrexate in Chinese pediatric patients with medulloblastoma

Abstract

Methotrexate (MTX) pharmacokinetics has substantial inter-individual variability and toxicity. In children with medulloblastoma treated with high-dose methotrexate (HD-MTX), the pharmacokinetic properties of methotrexate have not been established. A total of 660 serum samples from 105 pediatric patients with medulloblastoma were included in a population pharmacokinetic (PPK) analysis of methotrexate by using the nonlinear mixed-effects modeling method. The basic onecompartment population pharmacokinetic model was established by NONMEM software and the first-order conditional estimation (FOCE) method, and the final covariate model was obtained by the stepwise regression method. Weight (WT), creatinine clearance (CrCL), and whether the treatment was combined with dexamethasone (DEX) were covariates that had significant effects on the clearance rate (CL) of the model. The pharmacokinetic equation of CL in the final covariate model was as follows: CL i = 9.23× (1 + 0.0005× (θ CrCL -105.78)) × (1 + 0.0017× (θ WT -16)) × e ηcl,i (L/h), IF (θ DEX ) CL i = 1.19× CL i (L/h). The estimation accuracy of all pharmacokinetic parameters were acceptable (relative standard error < 14.74%). The goodness-of-fit diagram and bootstrap tests indicated that the final PPK model was stable with acceptable predictive ability. The PPK model may be useful for determining personalized medication levels in pediatric medulloblastoma patients undergoing HD-MTX therapy. K E Y W O R D S medulloblastoma, methotrexate, pediatric patients, personalized medicine, population pharmacokinetics

Insights from a pharmacometric analysis of HDMTX in adults with cancer: Clinically relevant covariates for application in precision dosing

“…Model-informed precision dosing is supported by the population approach, which leverages individual characteristics as parameters to predict more precisely the pharmacokinetic and pharmacodynamic outcomes and quantify the risk of severe adverse events. 5 Several HDMTX population pharmacokinetic models have been reported for paediatric patients, mainly with ALL or osteosarcoma, [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] others were developed for adult patients, [21][22][23][24][25][26][27][28][29][30] and few have described HDMTX pharmacokinetics in children and adults simultaneously. 27,[31][32][33][34] To date, these models reflect the high inter-and intraindividual variability linked to chemotherapeutic protocols and patient physiological and pathophysiological characteristics.…”

Population Pharmacokinetics of High-Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia

“…The antileukemic effect of MTX is attributed to its competitive inhibition of dihydrofolate reductase (Galivan, 1980;Schmiegelow, 2009). HD-MTX is defined as a dose higher than 500 mg/m 2 , which could elicit a broad range of antitumor activities (Evans et al, 1986;Howard et al, 2016;Kawakatsu et al, 2019;Shi et al, 2020). It has been reported that HD-MTX can reduce the relapse rate, increase the event-free survival rate, and suppress the development of central nervous system (CNS) leukemia in childhood ALL (Balis et al, 1985;Evans et al, 1986).…”

External Evaluation of Population Pharmacokinetic Models of Methotrexate for Model-Informed Precision Dosing in Pediatric Patients with Acute Lymphoid Leukemia

“…Among them, six studies included ALL patients greater than 13 years or infants and were excluded for further analysis [ 18 , 31 , 32 , 33 , 34 , 35 , 37 ]. In addition, one PopPK study was conducted on pediatric patients with osteosarcoma and was also excluded [ 38 ]. Finally, six PopPK models of MTX in ALL children were included for the external evaluation [ 11 , 19 , 20 , 21 , 26 , 36 ].…”