Low Serum Albumin Level Is a Risk Factor for Delayed Methotrexate Elimination in High-Dose Methotrexate Treatment

Kataoka, Tatsuo; Sakurashita, Hiroshi; Kajikawa, K.; Saeki, Yasuyuki; Taogoshi, Takanori; Matsuo, Hiroaki

doi:10.1177/1060028021992767

Cited by 10 publications

(8 citation statements)

References 21 publications

(46 reference statements)

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“…Several reports have linked the effects of albumin and hypoalbuminemia to altered MTX PKs. 13,[18][19][20][21] Mainly, these reports support the reduction of MTX CL with decreasing albumin. Our parameterization for severe hypoalbuminemia on MTX CL resulted in an estimated ~2% reduction in MTX clearance (Table S1), and did not significantly improve the description of the data.…”

Section: -H (μM)supporting

confidence: 62%

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Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

Taylor,

Miller,

Poweleit

et al. 2023

Clinical Translational Sci

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The MTXPK.org webtool was launched in December 2019 and was developed to facilitate model‐informed supportive care and optimal use of glucarpidase following the administration of high‐dose methotrexate (HDMTX). One limitation identified during the original development of the MTXPK.org tool was the perceived generalizability because the modeled population comprised solely of Nordic pediatric patients receiving 24‐h infusions for the treatment of acute lymphoblastic leukemia. The goal of our study is to describe the pharmacokinetics of HDMTX from a diverse patient population (e.g., races, ethnicity, indications for methotrexate, and variable infusion durations) and identify meaningful factors that account for methotrexate variability and improve the model's performance. To do this, retrospectively analyzed pharmacokinetic and toxicity data from pediatric and adolescent young adult patients who were receiving HDMTX (>0.5 g/m2) for the treatment of a cancer diagnosis from three pediatric medical centers. We performed population pharmacokinetic modeling referencing the original MTXPK.org NONMEM model (includes body surface area and serum creatinine as covariates) on 1668 patients, 7506 administrations of HDMTX, and 30,250 concentrations. Our results support the parameterizations of short infusion duration (<8 h) and the presence of Down syndrome on methotrexate clearance, the parameterization of severe hypoalbuminemia (<2.5 g/dL) on the intercompartmental clearance (Q2 and Q3), and the parameterization of pleural effusion on the volume of distribution (V1 and V2). These novel parameterizations will increase the generalizability of the MTXPK.org model once they are added to the webtool.

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Section: -H (μM)supporting

confidence: 62%

“…Circulating MTX is 50%–60% bound to albumin, 17 which suggests that a decrease in serum albumin would increase the amount of free (unbound) MTX. Several reports have linked the effects of albumin and hypoalbuminemia to altered MTX PKs 13,18–21 . Mainly, these reports support the reduction of MTX CL with decreasing albumin.…”

Section: Discussionmentioning

confidence: 82%

Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

Taylor,

Miller,

Poweleit

et al. 2023

Clinical Translational Sci

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“…The administration of high-dose methotrexate (MTX) is considered safe in patients who have low levels of albumin, provided that suitable leucovorin rescue and enough supportive care are provided. 16 In research done by Kataoka et al (year), a cohort of 74 patients was examined, revealing the identification of serum albumin as a significant risk factor. The analysis conducted involved both univariate and multivariate approaches, which provided insights into the relationship between low ALB levels (<3.7 g/dL) and types of cancer with delayed MTX elimination.…”

Section: Discussionmentioning

confidence: 99%

Influence of Hypoalbuminemia on Methotrexate Clearance in Children Receiving High Dose Methotrexate Therapy

Batool,

Yasmeen,

Tariq

et al. 2023

PJMHS

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Aim: Methotrexate, a structural counterpart of folic acid, is well recognized as a very efficacious pharmaceutical agent utilized in the treatment of several pediatric oncological conditions. A high-dose methotrexate is employed as a therapeutic intervention for a diverse range of malignant conditions including leukemia, lymphomas, and osteosarcoma. Hypoalbuminemia also decreases the methotrexate clearance leading to increased toxicity. Objective: To determine the frequency of side effects among patients receiving high dose methotrexate therapy based on baseline albumin levels. Study Design: A quasi-experimental trial was conducted at the Pakistan Institute of Medical Sciences, Islamabad, from January 1, 2023, to July 31, 2023. A total of thirty-four children receiving HDMTX were enrolled in the study. Albumin level, grade of liver toxicity, renal function tests, gastrointestinal and neurological toxicity, and mucositis were noted. Length of stay and methotrexate level at 24 hours were also noted. All the information was recorded in proforma.

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“…Hypoalbuminemia is reportedly associated with a significantly increased time for MTX clearance ( Reiss et al, 2016 ). Therefore, the reduction of ALB is a risk factor for delayed MTX elimination in HD-MTX monotherapy ( Kataoka et al, 2021 ). In the final model, a reduction in ALB from 50.0 g L −1 to 24.0 g L −1 may result in a 22.7% decrease in MTX CL/ F .…”

Section: Discussionmentioning

confidence: 99%

Evaluation and Application of Population Pharmacokinetic Models for Identifying Delayed Methotrexate Elimination in Patients With Primary Central Nervous System Lymphoma

Mao

et al. 2022

Front. Pharmacol.

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Objective: Several population pharmacokinetic (popPK) models have been developed to determine the sources of methotrexate (MTX) PK variability. It remains unknown if these published models are precise enough for use or if a new model needs to be built. The aims of this study were to 1) assess the predictability of published models and 2) analyze the potential risk factors for delayed MTX elimination.Methods: A total of 1458 MTX plasma concentrations, including 377 courses (1–17 per patient), were collected from 77 patients who were receiving high-dose MTX for the treatment of primary central nervous system lymphoma in Huashan Hospital. PopPK analysis was performed using the NONMEM® software package. Previously published popPK models were selected and rebuilt. A new popPK model was then constructed to screen potential covariates using a stepwise approach. The covariates were included based on the combination of theoretical mechanisms and data properties. Goodness-of-fit plots, bootstrap, and prediction- and simulation-based diagnostics were used to determine the stability and predictive performance of both the published and newly built models. Monte Carlo simulations were conducted to qualify the influence of risk factors on the incidence of delayed elimination.Results: Among the eight evaluated published models, none presented acceptable values of bias or inaccuracy. A two-compartment model was employed in the newly built model to describe the PK of MTX. The estimated mean clearance (CL/F) was 4.91 L h−1 (relative standard error: 3.7%). Creatinine clearance, albumin, and age were identified as covariates of MTX CL/F. The median and median absolute prediction errors of the final model were -10.2 and 36.4%, respectively. Results of goodness-of-fit plots, bootstrap, and prediction-corrected visual predictive checks indicated the high predictability of the final model.Conclusions: Current published models are not sufficiently reliable for cross-center use. The elderly patients and those with renal dysfunction, hypoalbuminemia are at higher risk of delayed elimination.

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Low Serum Albumin Level Is a Risk Factor for Delayed Methotrexate Elimination in High-Dose Methotrexate Treatment

Cited by 10 publications

References 21 publications

Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

Influence of Hypoalbuminemia on Methotrexate Clearance in Children Receiving High Dose Methotrexate Therapy

Evaluation and Application of Population Pharmacokinetic Models for Identifying Delayed Methotrexate Elimination in Patients With Primary Central Nervous System Lymphoma

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