Acotrexed, contains Pemetrexed is a multi-targeted antifolate chemotherapy drug primarily used to treat certain types of lung cancer and mesothelioma. It works by inhibiting enzymes involved in folate metabolism, which are necessary for DNA synthesis and cell replication in cancer cells.

Mechanism of Action

Pemetrexed interferes with cancer cell growth by inhibiting three key enzymes involved in folate metabolism:

• Thymidylate Synthase (TS)

• Dihydrofolate Reductase (DHFR)

• Glycinamide Ribonucleotide Formyltransferase (GARFT)

By inhibiting these enzymes, pemetrexed disrupts DNA and RNA synthesis, preventing cancer cells from multiplying and ultimately leading to cell death.

Indications

Pemetrexed is approved for the treatment of:

Non-Small Cell Lung Cancer (NSCLC)

• First-line treatment for non-squamous NSCLC in combination with cisplatin

• Maintenance therapy for advanced NSCLC

• Second-line therapy for recurrent NSCLC

Malignant Pleural Mesothelioma (MPM)

• First-line treatment in combination with cisplatin for patients who are not candidates for surgery.

Pemetrexed is a highly effective chemotherapy drug for non-squamous NSCLC and malignant pleural mesothelioma. With proper supplementation, careful monitoring, and supportive care, its side effects can be managed, allowing patients to benefit from improved survival and quality of life. However, physicians must carefully assess kidney function, drug interactions, and individual patient factors before prescribing pemetrexed. Ongoing research may expand its applications in the future.

Dosage and Administration

Recommended Dosage

Pemetrexed is administered as an intravenous (IV) infusion. The standard dosage varies based on the condition being treated:

• NSCLC (First-line, in combination with cisplatin): 500 mg/m² IV on Day 1 of each 21-day cycle.

• NSCLC (Maintenance or Second-line monotherapy): 500 mg/m² IV on Day 1 of each 21-day cycle.

• Malignant Pleural Mesothelioma (MPM, in combination with cisplatin): 500 mg/m² IV on Day 1 of each 21-day cycle.

Pre-medications and Supplementation

To reduce toxicity and side effects, patients should receive:

• Folic Acid (350-1000 mcg daily) starting at least 7 days before the first dose and continuing for 21 days after the last dose.

• Vitamin B12 (1000 mcg intramuscularly) at least 7 days before the first dose and once every 9 weeks.

• Corticosteroids (e.g., dexamethasone 4 mg twice daily) on the day before, the day of, and the day after treatment to reduce skin-related side effects.

Efficacy and Clinical Studies

1. Non-Small Cell Lung Cancer (NSCLC)

Clinical trials have demonstrated that pemetrexed, in combination with cisplatin, improves overall survival and progression-free survival in patients with advanced non-squamous NSCLC. It is particularly effective in non-squamous histology but not recommended for squamous cell carcinoma due to lower efficacy.

2. Malignant Pleural Mesothelioma (MPM)

A pivotal study showed that pemetrexed plus cisplatin significantly improved median survival compared to cisplatin alone in patients with malignant pleural mesothelioma.

Side Effects and Safety Profile

Common Side Effects:

• Fatigue

• Nausea and vomiting

• Loss of appetite

• Rash and skin reactions

• Anemia and low white blood cell counts (neutropenia)

• Diarrhea or constipation

• Mucositis (mouth sores)

Serious Side Effects:

• Myelosuppression: Decrease in white blood cells, red blood cells, and platelets, increasing the risk of infections and anemia.

• Kidney Toxicity: Patients with pre-existing kidney issues require dose adjustments.

• Liver Dysfunction: Periodic liver function tests are recommended.

• Interstitial Lung Disease: Rare but potentially fatal inflammation of lung tissue.

Managing Side Effects:

• Regular blood tests to monitor liver, kidney, and bone marrow function.

• Adequate hydration and kidney function monitoring before and after administration.

• Anti-nausea medications (e.g., ondansetron) to reduce vomiting.

• Use of hematopoietic growth factors if needed to manage neutropenia.

Contraindications and Precautions

Contraindications:

• Severe kidney impairment (creatinine clearance < 45 mL/min)

• Hypersensitivity to pemetrexed or any formulation components

• Pregnancy (Category D; can cause fetal harm)

• Breastfeeding (should be discontinued during treatment)

Precautions:

• Use with caution in elderly patients, as they may experience more severe toxicity.

• Patients with a history of lung disease or pulmonary fibrosis should be closely monitored.

• Avoid use with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with impaired kidney function due to increased toxicity risk.

Drug Interactions

• NSAIDs (e.g., ibuprofen, naproxen): Can delay pemetrexed clearance, increasing toxicity risk.

• Nephrotoxic drugs (e.g., aminoglycosides, contrast agents): Can increase the risk of kidney damage.

• Live vaccines: Should be avoided due to immunosuppressive effects of chemotherapy.

• Probenecid and Penicillins: May affect renal clearance of pemetrexed, requiring dose adjustments.

Use in Special Populations

1. Pregnancy and Breastfeeding

• Pemetrexed is classified as Pregnancy Category D and may cause fetal harm.

• Breastfeeding is not recommended during treatment due to the potential for serious adverse reactions in infants.

2. Pediatric and Geriatric Use

• The safety and efficacy of pemetrexed in pediatric patients have not been established.

• In elderly patients (≥65 years), increased monitoring is required due to a higher risk of myelosuppression and other toxicities.