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    Pemetrexed: Folic acid and VB12 applied 1 week in advance or at the same time?

    • Last Update: 2022-05-20
    • Source: Internet
    • Author: User
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    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
    .

    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
    .
    Lung Cancer Prevention

     

     

    1.
    Mechanism of Action

    1.
    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

    .
    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

    .
    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:  
    • ANC≥1500 cells/mm3

    • Platelet count ≥100000 cells/mm3

    • CrCl≥45 ml/min

    • 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/mm3
  • Platelet count ≥100000 cells/mm3

  • Platelet count ≥100000 cells/mm3

    Platelet count ≥100000 cells/mm3
  • CrCl≥45 ml/min

  • CrCl≥45 ml/min

    CrCl≥45 ml/min
  • Total bilirubin ≤ 1.
    5 times the upper limit of normal

  • Total bilirubin ≤ 1.
    5 times the upper limit of normal

    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)

  • 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:
      

    • ANC: Absolute Neutrophil Count Absolute Value

    • CrCl: creatinine clearance

    • ALP: Alkaline Phosphatase

    • AST: aspartate aminotransferase

    • ALT: alanine aminotransferase

  • ANC: Absolute Neutrophil Count Absolute Value

  • ANC: Absolute Neutrophil Count Absolute Value

    ANC: Absolute Neutrophil Count Absolute Value
  • CrCl: creatinine clearance

  • CrCl: creatinine clearance

    CrCl: creatinine clearance
  • ALP: Alkaline Phosphatase

  • ALP: Alkaline Phosphatase

    ALP: Alkaline Phosphatase
  • AST: aspartate aminotransferase

  • AST: aspartate aminotransferase

    AST: aspartate aminotransferase
  • ALT: alanine aminotransferase

  • ALT: alanine aminotransferase

    ALT: alanine aminotransferase

    references:

    references:

    1.
    Lexicomp Online, Lexi-Drugs Online.
    Waltham, MA: UpToDate, Inc.
    ; April 1, 2022.
    https://online.
    lexi.
    com.
    Accessed April 18, 2022.

    1.
    Lexicomp Online, Lexi-Drugs Online.
    Waltham, MA: UpToDate, Inc.
    ; April 1, 2022.
    https://online.
    lexi.
    com.
    Accessed April 18, 2022.

    2.
    Drug Instructions, Pemetrexed Disodium, AccessedApril 18, 2022.

    2.
    Drug Instructions, Pemetrexed Disodium, AccessedApril 18, 2022.

    3.
    Niyikiza C, Baker SD, Seitz DE, et al.
    Homocysteine ​​and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy.
    Mol Cancer Ther.
    2002;1(7):545-552.

    3.
    Niyikiza C, Baker SD, Seitz DE, et al.
    Homocysteine ​​and methylmalonic acid: markers to predict and avoid toxicity from pemetrexed therapy.
    Mol Cancer Ther.
    2002;1(7):545-552.

    4.
    Vogelzang NJ, Rusthoven JJ, Symanowski J, etal.
    Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
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    2003;21(14):2636-2644.
    doi:10.
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    2003.
    11.
    136

    4.
    Vogelzang NJ, Rusthoven JJ, Symanowski J, etal.
    Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.
    J ClinOncol.
    2003;21(14):2636-2644.
    doi:10.
    1200/JCO .
    2003.
    11.
    136

    5.
    Singh N, Baldi M, Kaur J, et al.
    Timing offolic acid/vitamin B12 supplementation and hematologic toxicity during first-line treatment of patients with nonsquamous non-small cell lung cancer using pemetrexed-based chemotherapy: The PEMVITASTART randomized trial.
    Cancer.
    2019;125(13):2203-2212.
    doi:10.
    1002/cncr.
    32028

    5.
    Singh N, Baldi M, Kaur J, et al.
    Timing offolic acid/vitamin B12 supplementation and hematologic toxicity during first-line treatment of patients with nonsquamous non-small cell lung cancer using pemetrexed-based chemotherapy: The PEMVITASTART randomized trial.
    Cancer.
    2019;125(13):2203-2212.
    doi:10.
    1002/cncr.
    32028

    6.
    Kim YS, Sun JM, Ahn JS, Ahn MJ, Park K.
    The optimal duration of vitamin supplementation prior to the first dose of pemetrexed in patients with non-small-cell lung cancer.
    Lung Cancer.
    2013;81(2):231 -235.
    doi:10.
    1016/j.
    lungcan.
    2013.
    04.
    011

    6.
    Kim YS, Sun JM, Ahn JS, Ahn MJ, Park K.
    The optimal duration of vitamin supplementation prior to the first dose of pemetrexed in patients with non-small-cell lung cancer.
    Lung Cancer.
    2013;81(2):231 -235.
    doi:10.
    1016/j.
    lungcan.
    2013.
    04.
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    7.
    Takagi Y, Hosomi Y, Sunami K, et al.
    Aprospective study of shortened vitamin supplementation prior tocisplatin-pemetrexed therapy for non-small cell lung cancer.
    Oncologist.
    2014;19(11):1194-1199.
    doi:10.
    1634/ theoncologist.
    2014-0221

    7.
    Takagi Y, Hosomi Y, Sunami K, et al.
    Aprospective study of shortened vitamin supplementation prior tocisplatin-pemetrexed therapy for non-small cell lung cancer.
    Oncologist.
    2014;19(11):1194-1199.
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    8.
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