Evidence-Based Medication Guideline for High-Dose Methotrexate
发布日期:
2024-04-22
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The “Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society” proposes that on the premise of multi-dimensional and full-process standardization of clinical medication, individualized dosing is the core content of the guideline, and pharmacogenetic testing and TDM are the “two arms” to realize personalized medication of HDMTX". Pre-medication genetic testing can stratify patients’ medication risks in advance. For example, severe reduction in methylenetetrahydrofolate reductase (MTHFR) activity indicates that the risk of HDMTX medication may increase; post-medication TDM can monitor the actual post-treatment blood concentration (CMTX), evaluate whether the target concentration range is reached and guide dose optimization to ensure that CMTX is maintained within a safe and effective therapeutic range. The overall framework of the recommendations is shown in Figure 1.




Evidence-Based Medication Guideline for High-Dose Methotrexate


01

The necessity of TDM after HDMTX medication

Routine TDM is recommended (strong recommendation, low-quality evidence). MTX varies greatly among individuals, CMTX is easily affected by multiple factors, and cancer patients are often accompanied by more concomitant medications. Implementing TDM and optimizing MTX and calcium folinate rescue dose can help improve the blood concentration compliance rate, reduce the incidence of adverse events, and improve the efficacy. A patient willingness survey showed that 95.24% of patients with hematological malignancies and 92.50% of patients with osteosarcoma were willing to receive TDM. Therefore, guidelines recommend routine TDM after HDMTX medication.

02

Assess the need for concomitant medications before drug use

It is recommended to fully evaluate concomitant medications and use the following medications with caution

(1) Drugs that affect MTX pharmacokinetics, including drugs that compete for plasma protein binding (such as aspirin, phenytoin) and drugs that affect MTX clearance (such as nonsteroidal anti-inflammatory drugs, penicillins, proton pump inhibitors, sulfonamides, Ciprofloxacin and vitamin C and other drugs that affect the pH of urine), etc

(2) Drugs that affect the pharmacodynamics of MTX, including drugs that cause hematotoxicity, nephrotoxicity, hepatotoxicity, as well as warfarin, cyclosporine, hydrochlorothiazide or other drugs that have adverse interactions with MTX. When the above drugs must be used in combination, CMTX and adverse events need to be closely monitored (strong recommendation, moderate-quality evidence).


03

TDM timing

For the 24-hour continuous infusion regimen, it is recommended to monitor CMTX once at least 24, 48, and 72 hours after the start of infusion until CMTX ≤ 0.1 ~ 0.2 µmol/L; when delayed excretion, acute kidney injury, or other serious adverse events occur, the monitoring interval should be shortened and the frequency of monitoring should be increased (strong recommendation, expert opinion).

04

C24h target range for patients with hematological malignancies

For children with ALL, the recommended target range for C24h (i.e., Css) at the end of the 24h infusion is 16 to 40 µmol/L (strong recommendation, moderate quality evidence).

05

C4-6h target range for patients with osteosarcoma

For patients with osteosarcoma, it is recommended that the target range of C4-6h  (i.e., Cmax) at the end of 4-6h infusion is 1000-1500 μmol/L (weak recommendation, low-quality evidence).

06

TDM-based dose adjustment

It is recommended that the MTX dose be adjusted individually based on TDM results and target therapeutic concentrations, combined with pharmacokinetic properties (weak recommendation, low-quality evidence). A summary of the recommendations related to TDM timing and target concentration for different infusion regimens is shown in Figure 2.



Summary

This guideline comprehensively reviews the evidence for methotrexate (MTX) drug treatment through evidence-based evaluation and qualitative and quantitative integration, and provides solid technical support for the individualized medication of high-dose methotrexate (HDMTX). This has far-reaching significance and important value in improving the accuracy of treatment and promoting patient recovery and health.



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Evidence-Based Medication Guideline for High-Dose Methotrexate





Evidence-Based Medication Guideline for High-Dose Methotrexate



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