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

Abstract

High-dose methotrexate (HD-MTX) is widely used in pediatric acute lymphoblastic leukemia (ALL) treatment regimens. In this study, we aimed to develop a population pharmacokinetic (PK) model of HD-MTX in Chinese pediatric patients with ALL for designing personalized dosage regimens. In total, 4,517 MTX serum concentration data for 311 pediatric patients with ALL, aged 0.75–15.2 years and under HD-MTX treatment, were retrospectively collected at a tertiary Children’s Hospital in China. The non-linear mixed-effect model was used to establish the population PK model, using NONMEM software. The potential covariate effects of age, body weight, and biochemical measurements (renal and liver function) on MTX PK disposition were investigated. The model was then evaluated using goodness-of-fit, visual predictive check. MTX PK disposition was described using a three-compartment model reasonable well. Body weight, implemented as a fixed allometric function on all clearance and volume of distribution parameters, showed a substantial improvement in model fit. The final population model demonstrated that the MTX clearance estimate in a typical child with body weight of 19 kg was 6.9 L/h and the central distribution of volume estimate was 20.7 L. The serum creatinine significantly affected the MTX clearance, with a 0.97% decrease in clearance per 1 μmol/L of serum creatinine. Other covariates (e.g., age, sex, bilirubin, albumin, aspartate transaminase, concomitant medication) did not significantly affect PK properties of MTX. The proposed population PK model could describe the MTX concentration data in Chinese pediatric patients with ALL. This population PK model combined with a maximum a posteriori Bayesian approach could be used to estimate individual PK parameters, and optimize personalized MTX therapy in target patients, thus aiming to reduce toxicity and improve treatment outcomes.

Clinical pharmacology of cytotoxic drugs in neonates and infants: Providing evidence-based dosing guidance

“…However, the results of these studies are conflicting. Several level 1 and level 2 studies describe no effect of age on pharmacokinetics after including other covariates, such as body weight (using allometric scaling), SLCO1B1 polymorphism, serum creatinine and/or treatment with dexamethasone [ [84] , [85] , [86] , [87] , [88] , [89] , [90] ]. Nevertheless, some level 1 studies did report an effect of age on high-dose methotrexate clearance or volume of distribution of the central compartment, even after normalising for body size [ [91] , [92] , [93] , [94] ].…”

“…Nevertheless, some level 1 studies did report an effect of age on high-dose methotrexate clearance or volume of distribution of the central compartment, even after normalising for body size [ [91] , [92] , [93] , [94] ]. In addition, one-, two- and three-compartment models have been published, suggesting a lack of consensus between studies [ 84 , 85 , [94] , [95] , [96] , [97] , [98] , [99] , [86] , [87] , [88] , [89] , [90] , [91] , [92] , [93] ]. These conflicting results could be related to variations in the method of drug analysis or differences in sampling times between the studies, with many models based on data obtained for routine patient care, for example, blood samples taken every 24 h to monitor the plasma concentrations for rescue therapy.…”

An Oral 3D Printed PLGA-Tocopherol PEG Succinate Nanocomposite Hydrogel for High-Dose Methotrexate Delivery in Maintenance Chemotherapy

“…To evaluate the printing accuracy between the different needle sizes, a 15 × 15 × 3 mm square template was designed, and square-shaped matrices were printed using stainless-steel precision tips. The printed matrices were measured with a digital caliper and the matrix area was calculated using Equation (3).…”

“…Methotrexate (MTX) is a commonly used chemotherapeutic drug for different types of cancer including childhood acute lymphocytic leukemia (ALL) and autoimmune disease [ 1 , 2 ]. A high dose (≥500 mg/m 2 ) of MTX (HDMTX) is used to achieve an effective plasma concentration in the target organs to treat several adult and pediatric malignancies, including ALL, osteosarcoma, and lymphomas [ 3 , 4 , 5 ]. MTX inhibits cancer cell growth by blocking the enzyme dihydrofolate reductase (DHFR), necessary for DNA synthesis [ 3 ].…”

“…A high dose (≥500 mg/m 2 ) of MTX (HDMTX) is used to achieve an effective plasma concentration in the target organs to treat several adult and pediatric malignancies, including ALL, osteosarcoma, and lymphomas [ 3 , 4 , 5 ]. MTX inhibits cancer cell growth by blocking the enzyme dihydrofolate reductase (DHFR), necessary for DNA synthesis [ 3 ]. However, variable pharmacokinetics profile intricate dosing schedules compromise the drugs’ bioavailability and therapeutic efficacy [ 6 , 7 ].…”