Pemetrexed is a commonly used antitumor drug, commonly used in the treatment of non-squamous non-small cell lung cancer and malignant pleural mesothelioma
.
This article summarizes the mechanism of action of pemetrexed, adverse reactions and related preventive medication and medication adjustment
.
.
This article summarizes the mechanism of action of pemetrexed, adverse reactions and related preventive medication and medication adjustment
.
Lung Cancer Prevention
1.
Mechanism of Action
Mechanism of action 1.
Mechanism of action
Pemetrexed is a multi-target folate antagonist Pemetrexed is a multi-target folate antagonist
.
The mechanism of action is shown in Figure 1
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Pemetrexed can enter cells through reduced folate carrier and folate-binding protein, and is converted into the form of polyglutamic acid in cells, inhibiting thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycine The action of amide nucleotide formyltransferase (GARFT), which in turn inhibits the bioresynthesis of thymine nucleotides and purine nucleotides, disrupts the replication of tumor cells
.
Figure 1.
Pemetrexed Mechanism of Action II, Adverse Reactions II, Adverse Reactions Table 1 summarizes the adverse reactions and clinical manifestations of pemetrexed .
Among them the hematological toxicity was the dose-limiting toxicity of pemetrexed .
Other more common (>10%) adverse reactions include fatigue, rash, scaling, nausea, vomiting, pharyngitis, etc.
Hematological toxicity is the dose - limiting toxicity of pemetrexed Table 1.
Adverse reactions of pemetrexed Depending on the severity of the reaction, preventive medication was used clinically .
The main prophylactic drugs include folic acid, vitamin B12, and dexamethasone , and the dosing regimen is summarized in Table 2 below .
Prophylaxis includes folic acid, vitamin B12, and dexamethasone Table 2.
Prophylactic regimen for pemetrexedTable 2.
Prophylaxis for pemetrexed
Early clinical trials found that increased hematologic toxicity and severe gastrointestinal reactions with pemetrexed were significantly associated with pretreatment homocysteine (Hcy) and methylmalonic acid (MMA) elevations in patients [3] [3]
.
The metabolism of homocysteine to methionine requires the participation of methionine synthase and 5-methyltetrahydrofolate
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Folic acid as a precursor of 5- methyltetrahydrofolate , vitamin B12 as a cofactor for methionine synthase is an important part of this metabolic process Cofactors are an important part of this metabolic process
.
Therefore, elevated homocysteine suggests possible deficiencies of folic acid and vitamin B12 .
Since methylmalonic acid metabolism is dependent on vitamin B12, elevated serum methylmalonic acid suggests vitamin B12 deficiency .
This suggests that the adverse reactions of pemetrexed are related to the deficiency of folic acid and vitamin B12 .
Subsequent clinical trials showed that the elevation of homocysteine suggested a possible deficiency of folic acid and vitamin B12 in the prophylactic use of folic acid and vitamin B12 can significantly reduce pemetrexed-related adverse reactions [4] .
The use of folic acid and vitamin B12 in prophylaxis can significantly reduce the adverse reactions associated with pemetrexed [4] [4] .
Should folic acid and vitamin B12 be given one week before the first cycle of pemetrexed? Should folic acid and vitamin B12 be given one week before the first cycle of pemetrexed? Controversy remains as to whether folic acid and vitamin B12 must be administered one week before the start of the first treatment cycle .
The current instructions for use of related drugs still recommend the use of folic acid and vitamin B12 within 7 days before pemetrexed is used
.
Those who questioned the plan said it would delay the use of antitumor drugs and not necessarily better prevent adverse reactions
.
The current instructions for use of related drugs still recommend the use of folic acid and vitamin B12 within 7 days before pemetrexed is used
.
A recent randomized trial [5] compared pemetrexed in combination with platinum in 150 patients with locally advanced or metastatic non-squamous non-small cell lung cancer before pemetrexed administration5-7.
The effect of folic acid and vitamin B12 supplementation on the occurrence of hematological toxicity at the start of the day and at the same time as administration .
The results showed that the co-administered group did not exhibit significantly more severe hematologic toxicity compared with the group supplemented with folic acid and vitamin B12 5-7 days before administration .
[5] Compared with the group supplemented with folic acid and vitamin B12 5-7 days before dosing, the co-administered group did not show significantly more severe hematologic toxicity It is worth mentioning that the data showed that before administration In the group that started prophylaxis on days 5-7, the levels of folic acid and vitamin B12 continued to rise at baseline, on the day of dosing, and after 3 treatment cycles, while homocysteine concentrations on the day of dosing were comparable to basal levels.
The homocysteine concentration decreased significantly after 3 cycles .
Prospective and retrospective studies [6-8] also suggest that pemetrexed-related toxicity is independent of the dosing interval between initiation of folic acid and vitamin B12 .
The optimization of dosing interval still needs more clinical evidence to support .
[6-8]
Pemetrexed-related toxicity was not related to the dosing interval between initiation of folic acid and vitamin B12
.
In addition to prophylaxis, biochemical tests should be performed on patients prior to initiation of pemetrexed therapy to ensure that:
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ANC≥1500 cells/mm3
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Platelet count ≥100000 cells/mm3
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CrCl≥45 ml/min
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Total bilirubin ≤ 1.
5 times the upper limit of normal -
ALP, AST and ALT ≤ 3 times the upper limit of normal, or 5 times the upper limit of normal (considered when the tumor affects the liver)
ANC≥1500 cells/mm3
ANC≥1500 cells/mm3
ANC≥1500 cells/mm3Platelet count ≥100000 cells/mm3
Platelet count ≥100000 cells/mm3
Platelet count ≥100000 cells/mm3CrCl≥45 ml/min
CrCl≥45 ml/min
CrCl≥45 ml/minTotal bilirubin ≤ 1.
5 times the upper limit of normal
Total bilirubin ≤ 1.
5 times the upper limit of normal
5 times the upper limit of normal
ALP, AST and ALT ≤ 3 times the upper limit of normal, or 5 times the upper limit of normal (considered when the tumor affects the liver)
ALP, AST and ALT ≤ 3 times the upper limit of normal, or 5 times the upper limit of normal (considered when the tumor affects the liver)
ALP, AST and ALT ≤ 3 times the upper limit of normal value, or 5 times the upper limit of normal value (can be considered when the tumor affects the liver).In addition, in the course of subsequent treatment, relevant biochemical indicators should be closely monitored, and training should be adjusted according to the occurrence of adverse reactions.
Dosage adjustment of metrexed
.
See Table 3 for a summary
.
Table 3.
Medication adjustment of pemetrexed based on adverse reactionsTable 3.
Medication adjustment of pemetrexed based on adverse reactions The dosing plan arranges preventive medication, and pays close attention to the relevant biochemical indicators and symptoms of the patient during the treatment cycle to adjust the dosing plan in time .
During the clinical use of pemetrexed, it is necessary to understand the relevant adverse reactions, arrange preventive medication according to the dosing plan, and pay close attention to the relevant biochemical indicators and symptoms of the patient during the treatment cycle and adjust the dosing plan in a timely manner .
abbreviation:
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ANC: Absolute Neutrophil Count Absolute Value
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CrCl: creatinine clearance
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ALP: Alkaline Phosphatase
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AST: aspartate aminotransferase
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ALT: alanine aminotransferase
ANC: Absolute Neutrophil Count Absolute Value
ANC: Absolute Neutrophil Count Absolute Value
ANC: Absolute Neutrophil Count Absolute ValueCrCl: creatinine clearance
CrCl: creatinine clearance
CrCl: creatinine clearanceALP: Alkaline Phosphatase
ALP: Alkaline Phosphatase
ALP: Alkaline PhosphataseAST: aspartate aminotransferase
AST: aspartate aminotransferase
AST: aspartate aminotransferaseALT: alanine aminotransferase
ALT: alanine aminotransferase
ALT: alanine aminotransferasereferences:
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