- Class: Antimetabolite – multitargeted antifolate.
Mechanism of Action (MOA)
- Structurally similar to folate → enters cells via reduced folate carrier (RFC).
- Inhibits multiple folate-dependent enzymes:
- Thymidylate synthase (TS)
- Dihydrofolate reductase (DHFR)
- Glycinamide ribonucleotide formyltransferase (GARFT)
- Net effect → ↓ thymidine and purine synthesis → inhibition of DNA and RNA synthesis.
- Cell cycle–specific: active in S-phase.
Clinical Uses
- Non–small cell lung cancer (NSCLC) (non-squamous histology):
- First-line in combination with cisplatin.
- Maintenance therapy after platinum-based chemotherapy.
- Malignant pleural mesothelioma (with cisplatin).
- Off-label: ovarian, breast, bladder, head/neck cancers.
Dosing (Adults)
- 500 mg/m² IV over 10 minutes q3w, usually with cisplatin.
- Supplementation required (to reduce severe toxicity):
- Folic acid: 400–1000 µg PO daily, starting 7 days before therapy and continuing until 21 days after last dose.
- Vitamin B12: 1 mg IM every 9 weeks (starting 1 week before first dose).
- Dexamethasone: 4 mg PO BID × 3 days (day before, day of, day after) → reduces rash incidence.
Toxicities
- Myelosuppression (DLT, especially neutropenia).
- Mucositis, stomatitis, pharyngitis.
- Nausea, vomiting, diarrhea, fatigue.
- Rash (reduced with dexamethasone).
- Renal toxicity (requires dose adjustment).
- Rare: interstitial pneumonitis, radiation recall.
Monitoring
- CBC with differential prior to each cycle.
- Renal function (dose adjust if CrCl < 45 mL/min).
- Hepatic function (use cautiously in hepatic impairment).
- Check vitamin supplementation adherence.
Summary
Pemetrexed (Alimta®) is a multitargeted antifolate widely used in non-squamous NSCLC and mesothelioma (with cisplatin). Requires folic acid + B12 supplementation + dexamethasone premedication to reduce severe myelosuppression, mucositis, and rash.