Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity

Rouw, Nikki de; Piet, Berber; Derijks, Hieronymus J.; Heuvel, Michel M. van den; Heine, Rob ter

doi:10.1007/s40264-021-01135-2

Cited by 13 publications

(9 citation statements)

References 74 publications

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“…It has been reported that PEM toxicity is related to the time above threshold concentration which is 0.110 mg/L for vitamin-supplemented patients ( Boosman et al, 2021 ). It was suggested to monitor the PEM concentration from 24 to 36 h after administration for toxicity management ( de Rouw et al, 2021b ). Through a simulation of concentration-time curve, we speculated that dosing regimens recommended for patients with different CrCl levels, might not bring additional toxicity risk for these patients if they receive vitamin-supplement.…”

Section: Discussionmentioning

confidence: 99%

“…Non-small cell lung carcinoma (NSCLC) accounts for 85% of all cases of lung carcinoma and the large majority of NSCLC patients are diagnosed at advanced stage with decreased 5-years survival rate. As an antifolate metabolic inhibitor, pemetrexed (PEM) is widely used in various tumors, especially NSCLC and mesothelioma ( de Rouw et al, 2021b ). Recently, immunotherapy in combination with PEM-based platinum or carboplatin showed a better survival benefit compared with chemotherapy alone ( Gandhi et al, 2018 ), and this combined treatment has also been recommended as first-line treatment for advanced NSCLC ( Ettinger et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Besides, it may also result in high blood drug concentration, which leads to intolerable or even life-threatening adverse reactions in patients. In the single agent trials with PEM, the most common adverse reactions are neutropenia, thrombocytopenia, reversible elevation of transaminase level, anorexia, diarrhea, mucositis, nausea, rash, and asthenia ( de Rouw et al, 2021b ). Therefore, it is necessary to monitor the drug concentration and optimize the dose in PEM chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetic study of pemetrexed in chinese primary advanced non-small cell lung carcinoma patients

et al. 2022

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The purposes of this study were to identify physiological and genetic factors that contributed to variability of pemetrexed (PEM) exposure and to optimize the dosing regimens for Chinese non-small cell lung carcinoma patients. A prospective population pharmacokinetics (PPK) research was performed in this population. The PEM concentrations of 192 plasma samples from 116 in-hospital patients were detected. All patients were genotyped for polymorphisms. The PPK model of PEM was developed. The pharmacokinetic behavior of PEM was described by a two-compartment model with first-order elimination. The population typical values were as follows: clearance (CL) 8.29 L/h, intercompartmental clearance (Q) 0.10 L/h, central volume of distribution (V1) 18.94 L and peripheral volume of distribution (V2) 5.12 L. Creatinine clearance (CrCl) was identified as a covariate to CL, and ERCC1 (rs3212986) and CYP3A5 (rs776746) gene polymorphisms as covariates to Q. By using empirical body surface area (BSA)-based dosing strategy, PEM exposure decreased with the elevation of CrCl. Contrarily, CrCl-based dosing strategy exhibited a satisfactory efficacy of achieving the target PEM exposure. BSA-based dosing regimen in current clinic practice is not suitable to achieve the target exposure in PEM chemotherapy of Chinese NSCLC patients. Alternatively, renal function-based dosing strategy is suggested.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetic study of pemetrexed in chinese primary advanced non-small cell lung carcinoma patients

et al. 2022

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“…Pemetrexed is a dose-dependent, multitargeted folate analog that suppresses tumor growth by impeding DNA synthesis and folate metabolism ( 13 ). Supplementary folic acid and vitamin B12 during chemotherapy reduce RBC toxicities while maintaining antitumor activity ( 14 , 15 ). The antineoplastic activity of cisplatin is mainly due to its ability to cross-link with DNA, thereby blocking transcription and replication ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: First case of pemetrexed plus cisplatin-induced immune hemolytic anemia in a patient with lung adenocarcinoma

Wang

et al. 2022

Front. Med.

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BackgroundDrug-induced immune hemolytic anemia (DIIHA) is a rare but potentially life-threatening drug-related complication. There are no previous reports of pemetrexed plus cisplatin as first-line chemotherapy for non-small cell lung cancer, resulting in DIIHA.Case presentationIn this report, a patient with advanced-stage lung adenocarcinoma developed severe immune hemolytic anemia 21 days after pemetrexed plus cisplatin chemotherapy. Laboratory findings showed severe hemolysis, including a rapid decrease in hemoglobin (HGB) and an elevated level of reticulocytes (Rets), indirect bilirubin (IBIL), and lactate dehydrogenase (LDH). A workup for the possibility of DIIHA was performed, including a direct antiglobulin test (DAT), a test in the presence of the soluble drug, and a drug-treated red blood cell (RBC) test. It showed a strongly positive (3+) result for anti-C3d but not for anti-immunoglobin G (IgG) in DAT. Enzyme-treated RBCs reacted weakly with the patient's serum and pemetrexed when complement was added. In addition, the patient's serum and normal sera were reactive with cisplatin-treated RBCs. However, eluates from the patient's RBCs and diluted normal sera were non-reactive with cisplatin-coated RBCs. Untreated and enzyme-treated RBCs reacted with the patient's serum in the presence of soluble cisplatin. In vitro serological tests suggested that complement-dependent pemetrexed antibodies and cisplatin-associated non-immunologic protein adsorption (NIPA) might combine to cause immune hemolytic anemia. The patient's anemia gradually recovered when pemetrexed and cisplatin were discontinued.ConclusionThis rare case demonstrated that complement-dependent pemetrexed antibodies and cisplatin-associated NIPA might occur simultaneously in a patient with DIIHA.

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“…Furthermore, oxaliplatin is an intravenously administered platinum-containing alkylating agent used for treating advanced colorectal cancer [ 5 ]. Pemetrexed is a cytostatic antifolate drug and a cornerstone treatment for lung cancer [ 6 ], and gemcitabine, which displays extensive and exact therapeutic effects, is considered the first-choice treatment in pancreatic cancer management [ 7 ]. However, patients with pancreatic cancer tend to be resistant to gemcitabine, failing to maintain the efficacy of the drug [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Lipocalin 2 may be a key factor regulating the chemosensitivity of pancreatic cancer to gemcitabine

Zhang¹,

Wu²,

Guo³

et al. 2022

Biochemistry and Biophysics Reports

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Mechanisms, Management and Prevention of Pemetrexed-Related Toxicity

Cited by 13 publications

References 74 publications

Population pharmacokinetic study of pemetrexed in chinese primary advanced non-small cell lung carcinoma patients

Population pharmacokinetic study of pemetrexed in chinese primary advanced non-small cell lung carcinoma patients

Case report: First case of pemetrexed plus cisplatin-induced immune hemolytic anemia in a patient with lung adenocarcinoma

Lipocalin 2 may be a key factor regulating the chemosensitivity of pancreatic cancer to gemcitabine

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