- Class: Antimetabolite – folate analog metabolic inhibitor.
- Subclass: Antifolate (like methotrexate, pemetrexed).
Mechanism of Action (MOA)
- Structurally designed to have enhanced affinity for the reduced folate carrier (RFC-1) → better uptake into tumor cells compared to methotrexate.
- Inhibits dihydrofolate reductase (DHFR) → ↓ tetrahydrofolate → blocks purine, thymidine, and DNA synthesis.
- Incorporates into polyglutamates (trapped inside tumor cells), increasing cytotoxicity.
- Cell cycle–specific: primarily active in the S-phase.
Clinical Uses
- Approved indication:
- Relapsed or refractory peripheral T-cell lymphoma (PTCL).
- Investigated in other lymphomas and solid tumors, but PTCL is the main clinical role.
Dosing (Adults)
- 30 mg/m² IV push over 3–5 minutes, weekly × 6 weeks, followed by 1-week rest (7-week cycle).
- Supplementation required:
- Folic acid 1 mg PO daily (starting 10 days before treatment → continue during therapy and 30 days after last dose).
- Vitamin B12 1 mg IM every 8–10 weeks (starting within 10 weeks prior to therapy).
- Supplementation helps reduce mucositis and hematologic toxicity.
Toxicities
- Dose-limiting: Mucositis/stomatitis.
- Myelosuppression (neutropenia, thrombocytopenia, anemia).
- Nausea, fatigue.
- Hepatotoxicity (↑ LFTs).
- Dermatologic: rash, pruritus.
- Serious: tumor lysis syndrome, infections.
Monitoring
- CBC with differential (weekly).
- LFTs, renal function (dose adjustments in renal impairment).
- Mucositis/stomatitis evaluation each cycle.
- Vitamin supplementation compliance (folic acid, B12).
Summary
Pralatrexate (Folotyn®) is a next-generation antifolate with high affinity for the folate carrier, approved for relapsed/refractory PTCL. Its hallmark concerns are mucositis and myelosuppression, mitigated by folic acid + vitamin B12 supplementation.