Relationship Between the Free and Total Methotrexate Plasma Concentration in Children and Application to Predict the Toxicity of HD-MTX

Abstract

High-dose methotrexate (HD-MTX) can be highly effective as well as extremely toxic. Many drug molecules can bind to plasma proteins to different extents in vivo, whereas only the free drug can reach the site of action to exert a pharmacological effect and cause toxicity. However, free MTX concentrations in plasma have not been reported. Traditional analyses of free drugs are both cumbersome and inaccurate. We collected 92 plasma samples from 52 children diagnosed with ALL or NHL or other lymphomas that were treated with HD-MTX. The hollow fiber centrifugal ultrafiltration (HFCF-UF) was used to prepare plasma samples for analysis of the free MTX concentration. Protein precipitation was employed to measure the total MTX concentration. The HFCF-UF is a simple method involving a step of ordinary centrifugation; the validation parameters for the methodological results were satisfactory and fell within the acceptance criteria. A linearity coefficient r2 of 0.910 was obtained for the correlation between the free and total MTX plasma concentrations in 92 plasma samples. However, the free and total MTX concentrations was only weakly correlated in 16 clinical plasma specimens with total MTX concentrations >2 μmol L−1 (r2 = 0.760). Both the free and total MTX concentrations at 42 h were negatively correlated with the creatinine clearance (CCr) level (P = 0.023, r = −0.236 for total MTX and P = 0.020, r = −0.241for free MTX, respectively). The free MTX concentration could not be accurately estimated from the total MTX concentration for patients with high MTX levels which are conditions under which toxic reactions are more likely to occur. High plasma MTX levels could become a predictor of the occurrence of MTX nephrotoxicity to draw people's attention. The proposed HFCF-UF method is a simple and accurate way to evaluate efficacy and toxicity in clinical therapeutic drug monitoring.

Analysis of the Efficacy of Multidrug Combination Chemotherapy Regimens for Osteosarcoma and the Management of Chemotherapeutic Reactions

“…HD-MTX has a dramatic effect on bone marrow cells, gastrointestinal tract, skin, oral mucosal cells, and hepatocytes, which have a short cell cycle and rapid proliferation rate, and can lead to a variety of adverse reactions such as bone marrow suppression, gastrointestinal reactions, mucositis, oral ulcers, and liver function damage [ 15 , 16 ], and the mortality of related adverse reactions is about 6% [ 17 ]. Therefore, the status of HD-MTX multidrug combined chemotherapy in the treatment of osteosarcoma is controversial.…”

“…Currently, the clinical use of MTX, ADR, PDD, and IFO in combination with chemotherapy for osteosarcoma can result in a 5-year survival rate of 44-65%, but some patients still have a poor prognosis [14]. In order to identify treatment strategies to improve osteosarcoma and to determine whether patients have a better or worse risk of local HD-MTX has a dramatic e ect on bone marrow cells, gastrointestinal tract, skin, oral mucosal cells, and hepatocytes, which have a short cell cycle and rapid proliferation rate, and can lead to a variety of adverse reactions such as bone marrow suppression, gastrointestinal reactions, mucositis, oral ulcers, and liver function damage [15,16], and the mortality of related adverse reactions is about 6% [17]. erefore, the status of HD-MTX multidrug combined chemotherapy in the treatment of osteosarcoma is controversial.…”

Factors influencing delayed high-dose methotrexate excretion and its correlation with adverse reactions after treatment in children with malignant hematological tumors

“…HDMTX (2–5 g/m 2 ) was dissolved in 0.9% sodium chloride injection or 5% dextrose injection; patients first received a loading dose of 1/10 of the total amount, which was rapidly infused intravenously over 0.5 hours, and the remaining dose was infused intravenously at an even rate over 23.5 hours. After 42 hours had passed since the first administration of MTX, CF was administered at a dose of 15 mg/m 2 q6h until the MTX concentration was <0.3 µmol/L ( 11 ). At least 12 hours before the delivery of HDMTX, monitoring of hydration, urine alkalinization, and maintenance of urine pH in the range of 7.0–8.0 was initiated.…”

Cinnamic acid mitigates methotrexate-induced lung fibrosis in rats: comparative study with pirfenidone

“…Methotrexate (MTX) has been widely prescribed in the treatment of a variety of malignant and inflammatory diseases for more than six decades and is still used for its remarkable therapeutic effects (Olsen et al 2014 ; Dong et al 2021 ). Furthermore, MTX possesses immunomodulatory properties due to its antimetabolite action, which interferes with folic acid metabolism.…”