Population Pharmacokinetic Study and Individual Dose Adjustments of High‐Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia or Osteosarcoma

Hui, Ka Ho Matthew; Chu, Ho Man; Fong, Pui Shan; Cheng, William; Lam, Tai Ning

doi:10.1002/jcph.1349

Cited by 30 publications

(36 citation statements)

References 43 publications

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“…The final model demonstrated that the MTX clearance estimate in a typical child with a body weight of 19 kg was 6.9 L/h. This value was similar to those reported previously: 8.8 L/h in 79 ALL pediatric patients with an average body weight of 25.3 kg by Piard et al (Piard et al, 2007), 7.87 L/h in 64 ALL pediatric patients with an average body weight of 25 kg (Faganel et al, 2011), and 7.73 L/h in 36 ALL pediatric patients with an average body weight of 23.4 kg (Hui et al, 2019). The central distribution of volume estimate in current study was 20.7 L, which was similar to that reported by a previous study (16.7 L) involving 64 pediatric patients with ALL/ML (Faganel et al, 2011) and somewhat higher than that reported by another pediatric study (9.3 L for a typical child with body weight of 20 kg) (Aumente et al, 2006).…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2021

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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.

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Section: Discussionsupporting

confidence: 91%

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

et al. 2021

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“…12,14,16 Therefore, eGFR (estimated glomerular filtration rate), Ccr, and Scr have been identified as important factors affecting MTX pharmacokinetics in various population pharmacokinetic analyses. 12,14,28,29 Scr and eGFR were also significant in the present study; however, the most important factor was Ccr. Therefore, Ccr based on Scr influences MTX pharmacokinetics in PCNSL patients.…”

Section: Discussionsupporting

confidence: 52%

Urine volume to hydration volume ratio is associated with pharmacokinetics of high‐dose methotrexate in patients with primary central nervous system lymphoma

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Morikochi

et al. 2021

Pharmacology Res & Perspec

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High‐dose methotrexate (HD‐MTX)‐based chemotherapy is the first‐line treatment for primary central nervous system lymphoma (PCNSL), but is associated with severe adverse effects, including myelosuppression and renal impairment. MTX is primarily excreted by the kidneys. Renal function calculated using serum creatinine (Scr) derived from muscle may be overestimated in elderly PCNSL patients. Therefore, we aimed to construct a population pharmacokinetic model in PCNSL patients and explore the factors associated with MTX clearance. Sixteen PCNSL patients (median age, 66 years) treated with HD‐MTX were included, and serum MTX concentrations were measured at 193 points in 49 courses. A population pharmacokinetic analysis was performed using NONMEM. A Monte Carlo simulation was conducted, in which serum MTX concentrations were stratified into three groups of creatine clearance (Ccr) (50, 75, and 100 ml/min) with three groups of the urine volume to hydration volume (UV/HV) ratio (<1, 1–2, and >2). The final model was constructed as follows: MTX clearance = 4.90·(Ccr/94.5) 0.456 ·(UV/HV) 0.458 . In the Monte Carlo simulation, serum MTX concentrations were below the standard values (10, 1, and 0.1 µM at 24, 48, and 72 h, respectively, after the start of the MTX administration) in most patients with UV/HV >2, even with Ccr of 50 ml/min. Conversely, half of the patients with UV/HV <1 and Ccr of 50 ml/min failed to achieve the standard values. The present results demonstrated that the UV/HV ratio was useful for describing the pharmacokinetics of MTX in PCNSL patients.

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“…The folate analogue MTX acts as an antineoplastic agent via competitive inhibition of dihydrofolate dehydrogenase, resulting in depletion of purines and thymidylate leading to impairment of DNA synthesis [ 2 , 3 ]. The drug can be administered via multiple routes of administrations and has a wide variation in dosing regimens including low (< 50 mg/m 2 ), intermediate (50–500 mg/m 2 ) and high (> 500 mg/m 2 ) dose regimens [ 1 , 4 ]. The pronounced inter-individual variability (IIV) of PK and toxicity of MTX [ 5 – 7 ] renders individualization of dosing regimens difficult.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

et al. 2021

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Background The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. Methods We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. Results Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95–5.92] L h− 1 and central volume of distribution of 4.29 [1.81–7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7–25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. Conclusion A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.

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Population Pharmacokinetic Study and Individual Dose Adjustments of High‐Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia or Osteosarcoma

Cited by 30 publications

References 43 publications

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

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

Urine volume to hydration volume ratio is associated with pharmacokinetics of high‐dose methotrexate in patients with primary central nervous system lymphoma

Evaluation of body-surface-area adjusted dosing of high-dose methotrexate by population pharmacokinetics in a large cohort of cancer patients

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