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Pemetrexed
Indications
Pemetrexed is an antifolate metabolic inhibitor approved by the U.S. Food Drug Administration (FDA) in 2004 for the treatment of malignant pleural mesothelioma.[1][2] Pemetrexed was developed by Edward C. Taylor and his team at Princeton University, who first synthesized lometrexol, the prototypical de novo purine antimetabolite.[3] However, lometrexol's structure was unstable, requiring the C-6 chiral center to be replaced with a pyrrolopyrimidine ring, creating a new molecule: N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid. Eli Lilly and Company brought this medication to the market and gave it a brand name.[4] Pemetrexed is an antineoplastic agent that can be given as a single agent or as part of combination therapy.
FDA-Approved Indications
- Malignant pleural mesothelioma [2][5][6][7]
- First-line treatment for stage I to stage IIIA, regardless of histologic type (as monotherapy)
- First-line treatment for unresectable tumors, regardless of histologic type or patients who are not candidates for surgery (in combination with cisplatin)
- As an adjuvant medication
- Non-small cell lung cancer (NSCLC), nonsquamous [8][9][10][11]
- Locally advanced or metastatic, nonsquamous NSCLC (in combination with cisplatin)
- Metastatic, nonsquamous NSCLC in patients with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations (in combination with platinum chemotherapy and pembrolizumab)
- Maintenance treatment in patients whose disease has not progressed after 4 cycles of platinum-based chemotherapy
- Patients with a history of prior chemotherapy (as monotherapy)
Off-Label Uses
Beyond its approved indications, pemetrexed has demonstrated effectiveness in treating other malignancies, highlighting its potential as a medication for managing challenging forms of cancer. Some of these are outlined below.
- Metastatic bladder cancer: Pemetrexed is used as monotherapy or in combination with cisplatin for metastatic transitional-cell bladder cancer.[12][13]
- Metastatic breast cancer: Pemetrexed is used as a first-line or second-line treatment for advanced or metastatic breast cancer.[14][15]
- Recurrent cervical cancer: Pemetrexed may be administered as a second-line treatment for recurrent or persistent cervical cancer.[16]
- Recurrent ovarian cancer: Pemetrexed is considered for recurrent or persistent platinum-resistant therapy of ovarian or primary peritoneal carcinoma.[1]
- Metastatic thymic malignancies: Pemetrexed is utilized as monotherapy in recurrent or metastatic thymoma or thymic carcinoma.[17][18]
Mechanism of Action
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Mechanism of Action
Pemetrexed inhibits the folate-dependent metabolic processes necessary for cellular replication. Specifically, it targets enzymes responsible for DNA and RNA synthesis, including thymidylate synthase (TS), dihydrofolate reductase (DHFR), glycinamide ribonucleotide formyltransferase (GARFT), and aminoimidazole carboxamide ribonucleotide formyltransferase (AICARFT), which disrupts the synthesis of purines, pyrimidines, and proteins.[3] Pemetrexed is transported into cells via membrane carriers, where it is converted to polyglutamate forms by the enzyme folylpolyglutamate synthetase. Polyglutamation is thought to occur more often in tumor cells than non-tumor cells. Polyglutamated metabolites have an increased intracellular half-life and prolonged drug action.[19]
Pharmacokinetics
The pharmacokinetics of pemetrexed comprise rapid intravenous (IV) administration, significant plasma protein binding, and renal metabolism. A thorough understanding of these pharmacokinetic characteristics facilitates this medication's safe and productive use in cancer therapy. With this understanding, healthcare providers can tailor dosing schedules and adeptly manage potential drug interactions or adverse reactions.[20]
Absorption: Pemetrexed is administered via intravenous (IV) formulation, bypassing the absorption phase. The IV infusion facilitates rapid and complete distribution of pemetrexed throughout the systemic circulation.
Distribution: Following IV administration, pemetrexed exhibits a steady-state volume of distribution of approximately 16.1 liters. Approximately 81% of the drug is bound to plasma proteins.
Metabolism: Pemetrexed is not metabolized to a significant extent.
Elimination: Pemetrexed is predominantly eliminated through renal excretion, with approximately 70% to 90% of the drug being excreted unchanged in the urine. In patients with consistent renal function, the total systemic clearance of pemetrexed is 91.8 mL/min, and its elimination half-life is approximately 3.5 hours. Pemetrexed is a substrate for organic anion transporter 3 (OAT3), a transporter protein primarily found in the kidney. This transporter is responsible for transporting pemetrexed from the bloodstream into renal tubular cells, facilitating its elimination from the body through urine.[21]
Administration
Available Forms and Strengths
Pemetrexed is available in 750 mg, 500 mg, 100 mg, and 1 mg formulations and may be administered intravenously in 25 mg/mL or 10 mg/mL concentrations.
Adult Dosage
The typical pemetrexed dose is 500 mg/m² every 3 weeks, depending on the indication. The clinician should always consult the drug package insert and institutional protocols before designing a dosing regimen for any patient. Pemetrexed is usually infused over 10 minutes, although this can vary depending on the specific indication or treatment protocol. When pemetrexed is part of a combination chemotherapy regimen, the exact administration order varies based on the protocol. Therefore, it is crucial to consult a protocol to determine the recommended sequence.
Before initiating pemetrexed therapy, it's recommended to start vitamin supplements to enhance their effectiveness and manage potential side effects. Premedication optimizes treatment outcomes while minimizing adverse effects, such as mucositis, gastrointestinal toxicity, and cutaneous reactions. Healthcare providers must monitor patients closely and adjust therapy based on individual responses.[22] A standard premedication regimen is outlined below.
Folic acid:
Dosage: 400 to 1,000 μg orally once daily
Start: 7 days before initiating pemetrexed therapy
Duration: Throughout the treatment period and for 21 days after the final pemetrexed dose
Vitamin B12:
Dosage: 1,000 μg intramuscularly (IM) once
Start: Administer once 7 days before initiating treatment
Duration: Repeat every 3 therapy cycles
Dexamethasone:
Dosage: 4 mg orally twice daily
Start: 24 hours before initiating pemetrexed therapy
Duration: Administer twice daily for 3 days
Specific Patient Populations
Hepatic impairment: Pemetrexed does not have any dose adjustments. Asymptomatic elevations of aspartate transaminase, alanine transaminase, and total bilirubin were observed during clinical trials; however, this did not affect the dose or schedule of pemetrexed administration.[23]
Renal impairment: Pemetrexed may increase toxic exposure in patients with kidney disease due to reduced plasma clearance. The recommended dose for a patient with a creatinine clearance (CrCl) ≥45 mL/min is 500 mg/m2 on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Patients with a CrCl of 45 to 60 mL/min may be at increased risk of hematologic, gastrointestinal, and kidney-related toxicity.[24] Using pemetrexed in patients with CrCl <45 mL/min is not recommended. Although pemetrexed may be removed through dialysis, it is not recommended for these patients.[25][26][27]
Pregnancy considerations: Based on animal studies and its mechanism of action, pemetrexed is not recommended during pregnancy due to its risk of causing fetal harm.[27]
Breastfeeding considerations: The presence or absence of pemetrexed in breast milk has not been established. Based on potential serious adverse effects, breastfeeding is not recommended during treatment and for 1 week after the last dose of pemetrexed.
Pediatric patients: The safety and efficacy of pemetrexed have not been established in pediatric patients.
Older patients: Clinical studies have revealed no differences between patients older and younger than 65. Refer to adult dosage.[28]
Adverse Effects
Adverse effects associated with pemetrexed are primarily caused by dose-related toxicities. One of the most frequent adverse events is myelosuppression. Patients have a higher risk of myelosuppression if they are not administered vitamin supplementation before, during, and after undergoing pemetrexed therapy.[29]
The following common adverse effects are categorized by system.[30][31]
Hematology
- Anemia
- Neutropenia
- Thrombocytopenia
Generalized symptoms
- Fatigue
Gastrointestinal
- Nausea
- Vomiting
- Anorexia
- Constipation
- Mucositis
- Diarrhea
- Heartburn
Neurology
- Sensory neuropathy
- Taste disturbance
Dermatology
- Alopecia
- Rash
Drug Interactions
Patients who receive frequent chemotherapy infusions may use non-steroidal anti-inflammatories for pain control management. Clinicians should avoid administering ibuprofen to patients receiving pemetrexed. Both medications are eliminated renally. Pemetrexed is a substrate for organic anion transporter 3 (OAT3), and ibuprofen is an organic anion transporter 3 (OAT3) inhibitor. Concomitant use may increase the risk of nephrotoxicity, myelosuppression, and gastrointestinal toxicity. In patients with a creatinine clearance between 45 mL/min and 79 mL/min, it is recommended to avoid ibuprofen 2 days before the first dose of pemetrexed and up to 2 days after the final dose in a cycle.
When administered concurrently with nephrotoxic medications, there is a risk of prolonging the clearance time for pemetrexed. Simultaneous administration of other renally-eliminated substances may lead to a delay in clearance.[21]
Contraindications
Pemetrexed is contraindicated in patients with a history of severe hypersensitivity reactions.
Box Warning and Precautions
Use caution in patients with a history of Stevens-Johnson syndrome or toxic epidermal necrolysis.[32] Pemetrexed should be used with caution in patients with pre-existing bone marrow suppression due to reported cases of severe myelosuppression. This medication may also cause nephrotoxicity, which may lead to renal failure. In patients with a history of pulmonary disease, severe interstitial pneumonitis has been reported. Other precautions for pemetrexed are radiation recall, teratogenicity, live vaccines, and increased risk of toxicity with ibuprofen.[21][33]
Monitoring
Patients receiving pemetrexed should be monitored with a complete blood count (CBC) with differential at day 1, 8, and 15 of each cycle. Female patients should be tested for pregnancy due to teratogenic properties. Before each cycle, baseline laboratory testing using renal function tests such as serum creatinine, creatinine clearance, blood urea nitrogen and total bilirubin, aspartate transaminase, and alanine transaminase should be obtained. Patients should also be monitored for adverse effects such as mucositis, pulmonary toxicity, dermatologic toxicity, and radiation recall. Pemetrexed should not be administered to patients with an absolute neutrophil count <1500 cells/mm3 or platelet count <100,000 cells/mm3. For nonhematologic toxicity grade 3 and above, pemetrexed should be held until the patient's CBC returns to baseline.[29]
Toxicity
Currently, no specific drugs are approved for the treatment of pemetrexed overdose. However, the data from animal studies suggests leucovorin may help alleviate the toxic effects associated with pemetrexed overdose. Symptoms of overdose include severe leukopenia, neutropenia (grade 4 lasting 3 days or more), and thrombocytopenia (grade 4). Additionally, leucovorin can be administered for bleeding associated with grade 3 thrombocytopenia and for managing grade 3 or 4 mucositis.[34]
Enhancing Healthcare Team Outcomes
The collaborative efforts of healthcare professionals in managing patients receiving pemetrexed are crucial for optimizing patient outcomes and ensuring the highest quality of care. Each healthcare team member plays a unique role in the care continuum, contributing their expertise to provide comprehensive support to patients and their families. Effective communication among team members promotes patient-centered care and facilitates seamless care coordination. Healthcare professionals can ensure patients receive the most appropriate and effective treatment while addressing their needs and preferences.
As frontline caregivers, nurses are pivotal in administering chemotherapy, monitoring patients for adverse reactions, and providing essential education and support throughout treatment. Their close interaction with patients positions them to identify signs and symptoms early, enabling timely intervention and improving patient safety.
With their specialized knowledge of medications and drug interactions, pharmacists are invaluable in optimizing medication regimens, minimizing adverse effects, and ensuring medication safety. Their collaboration with other healthcare professionals enhances the quality of care and contributes to better treatment outcomes.
Ethical considerations, such as informed consent and patient autonomy, must guide decision-making processes to uphold patients' rights and promote shared decision-making. Respecting patients' choices and preferences fosters trust and collaboration between healthcare professionals and patients, ultimately leading to better treatment adherence and outcomes.
Overall, multidisciplinary care guided by evidence-based practices, ethical principles, and effective communication is the cornerstone of successful cancer management with pemetrexed.
References
Vergote I, Calvert H, Kania M, Kaiser C, Zimmermann AH, Sehouli J. A randomised, double-blind, phase II study of two doses of pemetrexed in the treatment of platinum-resistant, epithelial ovarian or primary peritoneal cancer. European journal of cancer (Oxford, England : 1990). 2009 May:45(8):1415-23. doi: 10.1016/j.ejca.2008.12.013. Epub 2009 Jan 23 [PubMed PMID: 19168349]
Level 1 (high-level) evidenceVogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Jul 15:21(14):2636-44 [PubMed PMID: 12860938]
Chattopadhyay S, Moran RG, Goldman ID. Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Molecular cancer therapeutics. 2007 Feb:6(2):404-17 [PubMed PMID: 17308042]
Taylor EC, Kuhnt D, Shih C, Rinzel SM, Grindey GB, Barredo J, Jannatipour M, Moran RG. A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5- yl)ethyl]benzoyl]-L-glutamic acid, is an inhibitor of thymidylate synthase. Journal of medicinal chemistry. 1992 Nov 13:35(23):4450-4 [PubMed PMID: 1447744]
Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Marangolo M, Parra HJ, Santoro A. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Mar 20:24(9):1443-8 [PubMed PMID: 16549838]
Ceresoli GL, Zucali PA, Mencoboni M, Botta M, Grossi F, Cortinovis D, Zilembo N, Ripa C, Tiseo M, Favaretto AG, Soto-Parra H, De Vincenzo F, Bruzzone A, Lorenzi E, Gianoncelli L, Ercoli B, Giordano L, Santoro A. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. British journal of cancer. 2013 Aug 6:109(3):552-8. doi: 10.1038/bjc.2013.368. Epub 2013 Jul 16 [PubMed PMID: 23860535]
Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L, Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaïve patients with malignant pleural mesothelioma: results of the International Expanded Access Program. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2008 Jul:3(7):756-63. doi: 10.1097/JTO.0b013e31817c73d6. Epub [PubMed PMID: 18594322]
Kreuter M, Vansteenkiste J, Fischer JR, Eberhardt W, Zabeck H, Kollmeier J, Serke M, Frickhofen N, Reck M, Engel-Riedel W, Neumann S, Thomeer M, Schumann C, De Leyn P, Graeter T, Stamatis G, Zuna I, Griesinger F, Thomas M, TREAT investigators. Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study. Annals of oncology : official journal of the European Society for Medical Oncology. 2013 Apr:24(4):986-92. doi: 10.1093/annonc/mds578. Epub 2012 Nov 15 [PubMed PMID: 23161898]
Level 1 (high-level) evidenceChoy H, Gerber DE, Bradley JD, Iyengar P, Monberg M, Treat J, Govindan R, Koustensis A, Barker S, Obasaju C. Concurrent pemetrexed and radiation therapy in the treatment of patients with inoperable stage III non-small cell lung cancer: a systematic review of completed and ongoing studies. Lung cancer (Amsterdam, Netherlands). 2015 Mar:87(3):232-40. doi: 10.1016/j.lungcan.2014.12.003. Epub 2015 Jan 14 [PubMed PMID: 25650301]
Level 1 (high-level) evidenceScagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008 Jul 20:26(21):3543-51. doi: 10.1200/JCO.2007.15.0375. Epub 2008 May 27 [PubMed PMID: 18506025]
Karayama M, Inui N, Kuroishi S, Yokomura K, Toyoshima M, Shirai T, Masuda M, Yamada T, Yasuda K, Suda T, Chida K. Maintenance therapy with pemetrexed versus docetaxel after induction therapy with carboplatin and pemetrexed in chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer: a randomized, phase II study. Cancer chemotherapy and pharmacology. 2013 Aug:72(2):445-52. doi: 10.1007/s00280-013-2218-6. Epub 2013 Jun 27 [PubMed PMID: 23807323]
Level 1 (high-level) evidenceSweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS. Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Jul 20:24(21):3451-7 [PubMed PMID: 16849761]
Cao Y, He Y, Chen H, He S, Gu Y, Wang X, Chen B. Phase I study of gemcitabine-cisplatin versus pemetrexed cisplatin for patients with advanced or metastatic bladder cancer. Journal of B.U.ON. : official journal of the Balkan Union of Oncology. 2018 Mar-Apr:23(2):475-481 [PubMed PMID: 29745095]
Martin M, Spielmann M, Namer M, duBois A, Unger C, Dodwell D, Vodvarka P, Lind M, Calvert H, Casado A, Zelek L, Lluch A, Carrasco E, Kayitalire L, Zielinski C. Phase II study of pemetrexed in breast cancer patients pretreated with anthracyclines. Annals of oncology : official journal of the European Society for Medical Oncology. 2003 Aug:14(8):1246-52 [PubMed PMID: 12881387]
Llombart-Cussac A, Martin M, Harbeck N, Anghel RM, Eniu AE, Verrill MW, Neven P, De Grève J, Melemed AS, Clark R, Simms L, Kaiser CJ, Ma D. A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 Jun 15:13(12):3652-9 [PubMed PMID: 17575230]
Level 1 (high-level) evidenceLorusso D, Ferrandina G, Pignata S, Ludovisi M, Viganò R, Scalone S, Scollo P, Breda E, Pietragalla A, Scambia G. Evaluation of pemetrexed (Alimta, LY231514) as second-line chemotherapy in persistent or recurrent carcinoma of the cervix: the CERVIX 1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) Group. Annals of oncology : official journal of the European Society for Medical Oncology. 2010 Jan:21(1):61-6. doi: 10.1093/annonc/mdp266. Epub 2009 Jul 15 [PubMed PMID: 19605508]
Liang Y, Padda SK, Riess JW, West RB, Neal JW, Wakelee HA. Pemetrexed in patients with thymic malignancies previously treated with chemotherapy. Lung cancer (Amsterdam, Netherlands). 2015 Jan:87(1):34-8. doi: 10.1016/j.lungcan.2014.11.006. Epub 2014 Nov 15 [PubMed PMID: 25443273]
Gbolahan OB, Porter RF, Salter JT, Yiannoutsos C, Burns M, Chiorean EG, Loehrer PJ Sr. A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2018 Dec:13(12):1940-1948. doi: 10.1016/j.jtho.2018.07.094. Epub 2018 Aug 16 [PubMed PMID: 30121390]
Goldman ID, Zhao R. Molecular, biochemical, and cellular pharmacology of pemetrexed. Seminars in oncology. 2002 Dec:29(6 Suppl 18):3-17 [PubMed PMID: 12571805]
Ouellet D, Periclou AP, Johnson RD, Woodworth JR, Lalonde RL. Population pharmacokinetics of pemetrexed disodium (ALIMTA) in patients with cancer. Cancer chemotherapy and pharmacology. 2000:46(3):227-34 [PubMed PMID: 11021740]
Posada MM, Bacon JA, Schneck KB, Tirona RG, Kim RB, Higgins JW, Pak YA, Hall SD, Hillgren KM. Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling. Drug metabolism and disposition: the biological fate of chemicals. 2015 Mar:43(3):325-34. doi: 10.1124/dmd.114.059618. Epub 2014 Dec 12 [PubMed PMID: 25504564]
Singh N, Baldi M, Kaur J, Muthu V, Prasad KT, Behera D, Bal A, Gupta N, Kapoor R. Timing of folic 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 Jul 1:125(13):2203-2212. doi: 10.1002/cncr.32028. Epub 2019 Mar 2 [PubMed PMID: 30825389]
Level 1 (high-level) evidenceClarke SJ, Abratt R, Goedhals L, Boyer MJ, Millward MJ, Ackland SP. Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 2002 May:13(5):737-41 [PubMed PMID: 12075742]
Rusch VW. Pemetrexed and cisplatin for malignant pleural mesothelioma: a new standard of care? Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2003 Jul 15:21(14):2629-30 [PubMed PMID: 12860935]
Hill J, Vargo C, Smith M, Streeter J, Carbone DP. Safety of dose-reduced pemetrexed in patients with renal insufficiency. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2019 Jul:25(5):1125-1129. doi: 10.1177/1078155218780507. Epub 2018 Jun 5 [PubMed PMID: 29871545]
Mita AC, Sweeney CJ, Baker SD, Goetz A, Hammond LA, Patnaik A, Tolcher AW, Villalona-Calero M, Sandler A, Chaudhuri T, Molpus K, Latz JE, Simms L, Chaudhary AK, Johnson RD, Rowinsky EK, Takimoto CH. Phase I and pharmacokinetic study of pemetrexed administered every 3 weeks to advanced cancer patients with normal and impaired renal function. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2006 Feb 1:24(4):552-62 [PubMed PMID: 16391300]
de Rouw N, Croes S, Posthuma R, Agterhuis DE, Schoenmaekers JJAO, Derijks HJ, Burger DM, Dingemans AM, Ter Heine R. Pharmacokinetically-guided dosing of pemetrexed in a patient with renal impairment and a patient requiring hemodialysis. Lung cancer (Amsterdam, Netherlands). 2019 Apr:130():156-158. doi: 10.1016/j.lungcan.2019.01.018. Epub 2019 Feb 1 [PubMed PMID: 30885337]
Garassino MC, Gadgeel S, Speranza G, Felip E, Esteban E, Dómine M, Hochmair MJ, Powell SF, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Kurata T, Gray JE, Schwarzenberger P, Jensen E, Pietanza MC, Rodríguez-Abreu D. Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Apr 10:41(11):1992-1998. doi: 10.1200/JCO.22.01989. Epub 2023 Feb 21 [PubMed PMID: 36809080]
Adjei AA. Pharmacology and mechanism of action of pemetrexed. Clinical lung cancer. 2004 Apr:5 Suppl 2():S51-5 [PubMed PMID: 15117425]
Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. The Lancet. Oncology. 2012 Mar:13(3):247-55. doi: 10.1016/S1470-2045(12)70063-3. Epub 2012 Feb 16 [PubMed PMID: 22341744]
Level 1 (high-level) evidenceHanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, Tsao TC, Pless M, Muller T, Lim HL, Desch C, Szondy K, Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA Jr. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004 May 1:22(9):1589-97 [PubMed PMID: 15117980]
Level 1 (high-level) evidencePierard-Franchimont C, Lesuisse M, Humbert P, Delvenne P, Pierard GE. Toxic epidermal necrolysis and antifolate drugs in cancer chemotherapy. Current drug safety. 2012 Nov 1:7(5):357-60 [PubMed PMID: 23373549]
Kim KH, Song SY, Lim KH, Han SS, Kim SH, Cho JH, Park CW, Lee S, Lee HY. Interstitial Pneumonitis after Treatment with Pemetrexed for Non-small Cell Lung Cancer. Cancer research and treatment. 2013 Mar:45(1):74-7. doi: 10.4143/crt.2013.45.1.74. Epub 2013 Mar 31 [PubMed PMID: 23613674]
Gridelli C, Kaukel E, Gregorc V, Migliorino MR, Müller TR, Manegold C, Favaretto A, Martoni A, Caffo O, Schmittel A, Rossi A, Russo F, Peterson P, Muñoz M, Reck M. Single-agent pemetrexed or sequential pemetrexed/gemcitabine as front-line treatment of advanced non-small cell lung cancer in elderly patients or patients ineligible for platinum-based chemotherapy: a multicenter, randomized, phase II trial. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2007 Mar:2(3):221-9 [PubMed PMID: 17410045]
Level 1 (high-level) evidence