Population Pharmacokinetics of High-Dose Methotrexate in Patients With Primary Central Nervous System Lymphoma

Mei, Shenghui; Li, Xingang; Jiang, Xueyun; Yu, Kefu; Lin, Song; Zhao, Zhigang

doi:10.1016/j.xphs.2018.01.004

Cited by 30 publications

(59 citation statements)

References 35 publications

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“…These findings are in line with several population PK studies that document the close relationship between HD-MTX CL and kidney function. 28,[37][38][39][40] A population PK study in children and adults treated with HD-MTX for PCNSL revealed typical values of V 1 , CL, Q, and V 2 were 24.5 L, 6.67 L/hour, 0.047 L/hour, and 1.32 L, respectively; much lower than the values observed in our study. 37 These values match several studies that have been performed in Asian patients with smaller body habitus.…”

Section: Discussioncontrasting

confidence: 89%

“…28,[37][38][39][40] A population PK study in children and adults treated with HD-MTX for PCNSL revealed typical values of V 1 , CL, Q, and V 2 were 24.5 L, 6.67 L/hour, 0.047 L/hour, and 1.32 L, respectively; much lower than the values observed in our study. 37 These values match several studies that have been performed in Asian patients with smaller body habitus. [40][41][42] In contrast, a study in European patients reported base model estimates for V 1 , CL, Q, and V 2 as 34.0 L, 10.8 L/hour, 0.35 L/hour, and 6.3 L, respectively, which more closely match estimates from the present study.…”

Section: Discussioncontrasting

confidence: 89%

“…A population PK study in children and adults treated with HD‐MTX for PCNSL revealed typical values of V 1 , CL, Q, and V 2 were 24.5 L, 6.67 L/hour, 0.047 L/hour, and 1.32 L, respectively; much lower than the values observed in our study 37 . These values match several studies that have been performed in Asian patients with smaller body habitus 40‐42 .…”

Section: Discussionsupporting

confidence: 85%

“…Exclusion of patients without CT data was unlikely to have influenced our findings given that the exposure profiles among obese and non‐obese patients were almost superimposable. Our analyses were also limited to the first cycle of therapy; previous studies have demonstrated changes in PK of MTX between cycles 37‐42 . We chose to limit our analysis to the first cycle to reduce the potential influence of MTX use itself on body composition and CL that could cloud our interpretation of these relationships.…”

Section: Discussionmentioning

confidence: 99%

“…Our analyses were also limited to the first cycle of therapy; previous studies have demonstrated changes in PK of MTX between cycles. [37][38][39][40][41][42] We chose to limit our analysis to the first cycle to reduce the potential influence of MTX use itself on body composition and CL that could cloud our interpretation of these relationships. Furthermore, these metrics are likely to be less relevant once TDM is performed after the first cycle given that individual PK parameter estimates can inform dose management in subsequent cycles.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

et al. 2020

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Background High‐dose methotrexate (HD‐MTX) is used to treat primary central nervous system lymphoma (PCNSL), but potential differences in MTX clearance (CL) due to obesity have not been studied. We characterized the relationship between HD‐MTX CL and computed tomography (CT)‐generated body composition (morphomic), body size descriptors, and laboratory measurements in a cohort of obese and non‐obese patients with PCNSL. Methods Medical records from adult patients with PCNSL treated with HD‐MTX over a 10‐year period were queried. Individuals with CT data within 30 days of the first cycle of treatment were included. Population pharmacokinetic analysis was performed using a 2‐compartment base structural model. We specifically compared body surface area (BSA) to standard body size, morphomic, and renal function estimation methods as covariates of HD‐MTX CL. Results The final data set consisted of non‐obese (n=45) and obese (n=28) patients with 291 observations (3–7 samples per patient) with a mean (standard deviation) weight of 69.8 (11.6) kg and 104 (14.9) kg, respectively (p=0.0001). Vertebral body height was more informative than BSA of MTX CL. Similarly, a CL model incorporating age, albumin, and serum creatinine was more informative than kidney function equations and body size. The final model of MTX CL was based on age, albumin, serum creatinine, and vertebral body height. Conclusions Common clinical variables coupled with vertebral body height are more predictive of first cycle MTX CL than BSA, alternate body size descriptors, and commonly used kidney function equations.

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Section: Discussioncontrasting

confidence: 89%

Section: Discussioncontrasting

confidence: 89%

Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

et al. 2020

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

Shi

Liu

et al. 2020

Biopharm & Drug Disp

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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

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An ultrahigh‐performance liquid chromatography–tandem mass spectrometry method for quantification of methotrexate and 7‐hydroxy‐methotrexate and application for therapeutic drug monitoring in patients with central nervous system lymphoma

Huo,

Zhang,

Zhang

et al. 2023

Biomedical Chromatography

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A method using ultrahigh‐performance liquid chromatography–tandem mass spectrometry was developed, validated, and applied to simultaneously determine plasma methotrexate (MTX) and 7‐hydroxy‐methotrexate (7‐OH‐MTX) in 117 patients with central nervous system (CNS) lymphoma. The ion transitions utilized were m/z 455.2 > 308.2 for MTX and m/z 471.2 > 324.1 for 7‐OH‐MTX. Samples were prepared through protein precipitation using methanol. Chromatographic separation was achieved within 3.0 min on a CMS9030 column (Ruixi, 2.1 × 50 mm, 3 μm) through a gradient elution of methanol and a 10% ammonium acetate solution at a flow rate of 0.4 mL/min. The method demonstrated linearity in the concentration range of 0.05–10 μM for MTX and 0.25–50 μM for 7‐OH‐MTX. The intra‐ and inter‐day inaccuracy ranged from –7.38% to 7.83%, and the imprecision was less than 6.00% for both analytes. The recovery and matrix effect normalized by the internal standard (MTX‐D3) remained consistent. Both analytes remained stable under nine different storage conditions. In patients with CNS lymphoma, MTX levels at 12 h and 7‐OH‐MTX levels at 12, 36, and 60 h after dosing in individuals with impaired renal function were significantly higher compared with those with normal renal function. 7‐OH‐MTX could potentially serve as a superior indicator for nephrotoxicity compared with MTX.

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Population Pharmacokinetics of High-Dose Methotrexate in Patients With Primary Central Nervous System Lymphoma

Cited by 30 publications

References 35 publications

Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

Comparison of Body Size, Morphomics, and Kidney Function as Covariates of High‐Dose Methotrexate Clearance in Obese Adults with Primary Central Nervous System Lymphoma

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

An ultrahigh‐performance liquid chromatography–tandem mass spectrometry method for quantification of methotrexate and 7‐hydroxy‐methotrexate and application for therapeutic drug monitoring in patients with central nervous system lymphoma

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