Pralatrexate Injection (Folotyn™)
Pharmacology Update
Pralatrexate Injection (Folotyn™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.Drs. Elliott and Chan report no financial relationship to this field of study.
The FDA has approved the first treatment for relapsed or refractory peripheral T-cell lymphoma. Pralatrexate, an inhibitor of dihydrofolate reductase, was granted accelerated approval by the FDA. It will be marketed by Allos Therapeutics as Folotyn™.
Indications
Pralatrexate is indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL).1
Dosage
The recommended dose is 30 mg/m2 given as an intravenous push over 3-5 minutes once weekly for 6 weeks in 7-week cycles.1 The dose may be omitted or reduced based on patient tolerance. Omitted doses should not be made up at the end of the cycle and dose reductions should not be re-escalated.1 Dose reduction is based on mucositis and hematologic toxicity. Low-dose folic acid (1.0-1.25 mg) should be taken daily, started during the 10 days before the first dose of pralatrexate, and continued throughout therapy and for 30 days after the last dose of pralatrexate. Vitamin B12 (1 mg intramuscularly) should be started no more than 10 weeks before the first dose of pralatrexate and given every 8-10 weeks thereafter.1
Pralatrexate is supplied as 20 mg/mL in 1 mL and 2 mL vials.
Potential Advantages
Pralatrexate shows superior intracellular transport and accumulation compared to other antifolate agents.2
Potential Disadvantages
The most common adverse events are mucositis (70%), thrombocytopenia (41%), nausea (40%), fatigue (36%), and anemia (34%). The most common Grade 3 toxicities are mucositis (17%), thrombocytopenia (14%), anemia (15%), and neutropenia (13%).1 Concomitant administration with probenecid, NSAIDs, and trimethoprim/sulfamethaxazole may delay the renal clearance of pralatrexate.1
Comments
Pralatrexate is the newest antifolate agent to be approved. In vitro and in vivo models of human cancer suggest that the drug has better antitumor activity than methotrexate and pemetrexed.2 This may be related to better intracellular transport (high affinity for the reduced folate carrier type 1) and increased intracellular accumulation by enhanced polyglutamylation. The safety and efficacy of pralatrexate was based on an open-label, single-arm study in patients (n = 111) with histologically confirmed relapsed or refractory peripheral T-cell lymphoma.1 The primary efficacy endpoint was overall response (complete response, complete response unconfirmed, and partial response) using the International Workshop Criteria. The secondary endpoint was duration of response (first day of documented response to disease progression or death). The overall response was 27% (8% with complete response or complete response unconfirmed). The median duration of response was 287 days. Two-thirds of the responders responded within cycle 1. Improvement in progression-free survival or overall survival has not been established.
Clinical Implications
Peripheral T-cell lymphomas are biologically diverse but rare and aggressive types of non-Hodgkin's lymphoma.3 Most PTCL patients will relapse. Relapsed or refractory peripheral T-cell lymphoma is a disease with a poor prognosis with limited response to salvage therapy. Typically chemotherapy includes ifosfamide, carboplatin, and etoposide, followed by an autologous stem cell transplant.4 Other combinations include gemcita-bine, vinorelbine, and doxorubicin. Pralatrexate offers another therapeutic option and is the first drug approved for PTCL.
References
1. Folotyn Product Labeling. Westminster, CO: Allos Therapeutics, Inc.; September 2009.
2. Izbicka E, et al. Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers. Cancer Chemother Pharmacol 2009;64:993-999.
3. Savage KJ. Aggressive peripheral T-cell lymphomas (specified and unspecified types). Hematology Am Soc Hematol Educ Program 2005;267-277.
4. O'Connor OA; Lymphoma Research Foundation. Getting the Facts. Available at: www.lymphoma.org/atf/cf/%7B0363cdd6-51b5-427b-be48-e6af871acec9%7D/PTCL09.PDF. Accessed Oct. 23, 2009.
The FDA has approved the first treatment for relapsed or refractory peripheral T-cell lymphoma. Pralatrexate, an inhibitor of dihydrofolate reductase, was granted accelerated approval by the FDA. It will be marketed by Allos Therapeutics as Folotyn™.Subscribe Now for Access
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