Pemetrexed: multitarget folate antagonist cytostatic
Pemetrexed (brand names Alimta, generic) is a modern folate antagonist with multi target action. Unlike classical methotrexate, which primarily blocks dihydrofolate reductase, pemetrexed inhibits several key enzymes of folate dependent nucleotide synthesis. Introduced in 2004, it is standard in systemic therapy of non small cell lung cancer (non squamous) and malignant pleural mesothelioma.
A characteristic feature of pemetrexed is the mandatory pre and concomitant therapy with folic acid and vitamin B12, which markedly improves the toxicity profile and ensures tolerability.
Mechanism of action
Pemetrexed is a pyrrolopyrimidine analogue taken into cells via the reduced folate carrier and FRalpha. There it is polyglutamated by folylpolyglutamate synthetase, increasing intracellular retention and prolonging effect. Polyglutamated pemetrexed inhibits several key enzymes:
- Thymidylate synthase (main target): blocks DNA synthesis
- Dihydrofolate reductase: similar to methotrexate
- Glycinamide ribonucleotide formyltransferase (GARFT): inhibits purine synthesis
The result is comprehensive inhibition of nucleotide synthesis with arrest of cell division and apoptosis particularly in rapidly dividing tumour cells. Pre therapy with folic acid and vitamin B12 reduces toxicity to normal cells without significantly affecting antitumour activity.
Indications
- Non small cell lung cancer (NSCLC) non squamous: first line therapy in combination with cisplatin or carboplatin and pembrolizumab; maintenance therapy as monotherapy or with pembrolizumab
- Malignant pleural mesothelioma (MPM): first line therapy in combination with cisplatin
- Off label: some studies in other solid tumours
Pemetrexed is not effective in squamous cell carcinoma of the lung due to high thymidylate synthase expression in these tumours.
Dosing and administration
Standard dose: 500 mg per m² body surface intravenously as a 10 minute infusion on day 1 of every 21 day cycle.
Pre and concomitant therapy:
- Folic acid: 350 to 1,000 µg orally per day, starting 7 days before the first pemetrexed dose and continuously until 21 days after the last dose
- Vitamin B12: 1,000 µg intramuscularly, 1 to 3 weeks before the first dose and repeated every 9 weeks
- Dexamethasone: 4 mg twice daily on the day before infusion, on infusion day and the day after (rash prophylaxis)
Treatment is given in oncology centres with experienced teams. Close blood count and laboratory monitoring before each cycle.
Adverse effects
Very common: fatigue, anaemia, neutropenia, thrombocytopenia, nausea, vomiting, mucositis, diarrhoea, constipation, anorexia, rash.
Common: raised liver transaminases, raised creatinine, pneumonitis, conjunctivitis, taste changes, lacrimation.
Uncommon: tumour lysis syndrome, Stevens Johnson syndrome, severe hepatitis, acute kidney injury, severe pneumonitis up to lung failure.
Rare: bullous pemphigoid, hemiparesis, ischaemic colitis.
Important points:
- Consistent folic acid and vitamin B12 substitution markedly reduces haematological toxicity and mucositis
- With NSAID co medication monitor renal function closely, since NSAIDs can reduce pemetrexed clearance
- Adhere to steroid prophylaxis for rash
- Sudden dyspnoea or cough should raise suspicion of pneumonitis
Interactions
- NSAIDs (ibuprofen, diclofenac etc.): reduced pemetrexed clearance, increased toxicity, especially in renal impairment; with standard 500 mg per m² pause NSAIDs 2 days before and 2 days after pemetrexed
- Probenecid: reduced clearance
- Live vaccines: contraindicated during and several months after therapy
- Other myelotoxic agents: additive toxicity
- Radiotherapy: caution with closely timed combinations because of radiosensitisation
Special considerations
Pregnancy: contraindicated, markedly teratogenic. Reliable contraception during therapy and for at least 6 months after for both sexes.
Breastfeeding: contraindicated.
Renal impairment: not recommended at creatinine clearance below 45 ml/min.
Liver disease: use possible in moderate impairment, caution in severe.
Patient communication: pemetrexed is among the better tolerated cytostatics in modern oncology. Consistent folic acid and vitamin B12 intake and steroid prophylaxis ensure tolerability. Patients should be informed about typical adverse events such as fatigue, mucositis and rash, and about the importance of reporting symptoms such as dyspnoea or fever.
Related substances
- Methotrexate, classical folate antagonist
- Folinic acid, activated form of folic acid
- Etoposide, topoisomerase 2 inhibitor
- Sotorasib, KRAS G12C inhibitor in NSCLC
- Aflibercept, VEGF trap in oncology
Frequently asked questions
Why do I need folic acid and vitamin B12?
Pemetrexed acts on folate metabolism. Folic acid and vitamin B12 substitution markedly reduces toxicity to normal cells (mainly bone marrow and mucosa) without compromising antitumour activity. This pre treatment is mandatory and must be followed consistently.
Why no painkillers like ibuprofen?
NSAIDs can reduce renal clearance of pemetrexed, leading to higher levels and increased toxicity. With standard dose pemetrexed it is recommended to pause NSAIDs 2 days before and 2 days after infusion. Paracetamol is a safer alternative for pain in this phase.
Which tumours respond best?
Lung adenocarcinomas and malignant pleural mesotheliomas show the best efficacy. Pemetrexed is not approved in squamous cell carcinoma, since these tumours often have high thymidylate synthase levels and are therefore resistant.
How is response measured?
CT imaging every 6 to 12 weeks, clinical assessment, tumour markers. In maintenance therapy assessment focuses on stabilisation and quality of life. With progression therapy is moved to the next line.
Sources
- EMA Alimta (pemetrexed) EPAR
- BfArM German Federal Institute for Drugs and Medical Devices
- AWMF S3 guideline lung cancer and pleural mesothelioma
- Gelbe Liste pemetrexed monograph
Legal notice and disclaimer
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