Folotyn (pralatrexate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Pralatrexate, a folic acid antagonist, is an antineoplastic agent.
Pralatrexate, a 10-deazaaminopterin analog of methotrexate, is an antineoplastic agent. Pralatrexate differs structurally from methotrexate in that pralatrexate contains a carbon with a propargyl side chain instead of a nitrogen with a methyl side chain in the 10-position. This structural modification allows pralatrexate to selectively and efficiently enter cells expressing reduced-folate carrier type 1 (RFC-1), a protein that is overexpressed on fetal and certain cancer cell types (including some T-cell lymphomas).
In addition, the modified structure also allows pralatrexate to undergo enhanced intracellular polyglutamylation by the enzyme folylpolyglutamate synthetase (FPGS), resulting in enhanced retention and accumulation of the drug inside the cells; polyglutamylation is a time- and concentration-dependent process that occurs in tumor cells and, to a lesser extent, in normal tissues. Like methotrexate, polyglutamylated pralatrexate exerts its antineoplastic activity by disrupting folate-dependent metabolic processes that are essential for cell replication. Specifically, pralatrexate inhibits dihydrofolate reductase (DHFR), an enzyme involved in the synthesis of deoxythymidine and purine nucleotides.
Reduction in the pool of available nucleotides, primarily thymine and to a lesser extent adenine and guanine, interrupts DNA synthesis and induces S-phase arrest, resulting in cytostasis and apoptosis (programmed cell death).
In preclinical studies, pralatrexate demonstrated greater affinity for RFC-1 (resulting in enhanced intracellular transport), enhanced polyglutamylation (resulting in increased intracellular drug retention and accumulation), and improved cytotoxicity compared with other folic acid antagonists (e.g., methotrexate, pemetrexed). Down-regulation and/or inhibition of effective RFC-1 transport and/or polyglutamylation have been proposed as possible mechanisms of resistance to methotrexate and other folic acid antagonists.
Following rapid IV injection of pralatrexate (30 mg/m2 over 3-5 minutes) once weekly for 6 weeks in 7-week cycles, peak plasma concentration and area under the plasma concentration-time curve (AUC) of the drug increased proportionally with dose. In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins. Following multiple treatment cycles, no accumulation of pralatrexate was observed.
Pralatrexate is not substantially metabolized by phase I hepatic cytochrome P-450 (CYP) isoenzymes or phase II hepatic glucuronidases; the drug has low potential to induce or inhibit the activity of CYP isoenzymes. In vitro studies indicate that pralatrexate is not a substrate or inhibitor of the P-glycoprotein transport system. The terminal elimination half-life of pralatrexate is 12-18 hours.
Following a single rapid IV injection of pralatrexate (30 mg/m2 over 3-5 minutes), approximately 34% of pralatrexate is excreted unchanged in urine. Because of the contribution of renal excretion to overall clearance of pralatrexate, age-related decline in renal function may lead to a reduction in clearance of and corresponding increase in plasma exposure to the drug. In a population pharmacokinetic analysis, drug clearance decreased with decreasing creatinine clearance.
There was no substantial effect of gender on pharmacokinetics of pralatrexate.
USES: Pralatrexate is used to treat a certain type of cancer (peripheral T-Cell lymphoma-PTCL). Pralatrexate works by slowing or stopping the growth of cancer cells.
Generic name: pralatrexate
Pronunciation: (PRAL-a-TREX-ate)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Folotyn
Indications
The following indications are listed for Folotyn:
- Peripheral T-Cell Lymphoma
Dosing
After the initial dose, subsequent doses of pralatrexate should be adjusted based on severity of mucositis, hematologic counts (i.e., ANCs, platelet counts), and/or presence of other treatment-related toxicities (e.g., hepatotoxicity) determined on the day of treatment. Depending on the severity of the toxicity, subsequent doses of pralatrexate may be omitted and/or reduced, or pralatrexate therapy may be discontinued permanently. (See Tables 1, 2, and 3.) The manufacturer states that omitted doses should not be made up at the end of the treatment cycle; in addition, dosages reduced following drug-related adverse effects should not be re-escalated.
Table 1. Recommended Dosage Modification for Mucositis
Mucositis Grade on Day of Treatment Recommended Action Grade 2 Omit dose; when mucositis improves (to grade 1 or lower), resume pralatrexate at prior dose Grade 2 recurrence Omit dose; when mucositis improves (to grade 1 or lower), resume pralatrexate at a reduced dose of 20 mg/m2 Grade 3 Omit dose; when mucositis improves (to grade 1 or lower), resume pralatrexate at a reduced dose of 20 mg/m2 Grade 4 Discontinue pralatrexate permanently
Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0).
Table 2. Recommended Dosage Modification for Hematologic Toxicity
Blood Count on Day of Duration of Toxicity Recommended Action Treatment Platelet count 1 week Omit dose; when platelet <50,000/mm3 count >=50,000/mm3, resume pralatrexate at prior dose 2 weeks Omit dose; when platelet count >=50,000/mm3, resume pralatrexate at a reduced dose of 20 mg/m2 3 weeks Discontinue pralatrexate permanently ANC of 500-1000/mm3 1 week Omit dose; when ANC without fever >=1000/mm3, resume pralatrexate at prior dose ANC of 500-1000/mm3 with 1 week Omit dose; initiate fever or ANC <500/mm3 growth factor (e.g., filgrastim, sargramostim) support; when ANC >=1000/mm3, resume pralatrexate at prior dose and continue growth factor support 2 weeks or recurrence Omit dose; initiate growth factor (e.g., filgrastim, sargramostim) support; when ANC >=1000/mm3, resume treatment at a reduced dose of 20 mg/m2 and continue growth factor support 3 weeks or second Discontinue pralatrexate recurrence permanently
Table 3. Recommended Dosage Modification for Other Treatment-related Toxicities (e.g., Hepatotoxicity)
Toxicity Grade on Day of Treatment Recommended Action Grade 3 Omit dose; when toxicity improves (to grade 2 or lower), resume pralatrexate at a reduced dose of 20 mg/m2 Grade 4 Discontinue pralatrexate permanently
Pralatrexate is administered undiluted by rapid IV injection over 3-5 minutes into the side port of a free-flowing IV infusion of 0.9% sodium chloride injection.
The usual precautions for handling, preparing, and administering solutions of cytotoxic drugs should be observed with pralatrexate. The manufacturer recommends use of gloves and other protective clothing when handling the drug. If pralatrexate comes in contact with skin or mucosa, affected skin areas should be washed immediately and thoroughly with soap and water and affected mucosa should be thoroughly flushed with water.
The appropriate volume of pralatrexate 20-mg/mL injection should be aseptically withdrawn into a syringe for immediate use. Pralatrexate injection should not be diluted. Because pralatrexate injection contains no preservatives, any unused portions should be discarded.
Pralatrexate injection should be stored in the original carton at 2-8degreesC and protected from light until use. When stored in the original carton at room temperature, unopened vials of pralatrexate injection are stable for 72 hours; any vials left at room temperature for longer than 72 hours should be discarded.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
No formal drug interaction studies have been performed to date.
In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of cytochrome P-450 (CYP) isoenzymes. Pralatrexate also is not a substrate or inhibitor of the P-glycoprotein transport system.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
The manufacturer states that there are no known contraindications to the use of pralatrexate.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects of pralatrexate include mucositis, thrombocytopenia, nausea, and fatigue. Other common adverse effects reported in more than 20% of patients include anemia, constipation, pyrexia, edema, cough, epistaxis, vomiting, neutropenia, and diarrhea. The most common serious adverse effects of pralatrexate include pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of pralatrexate have not been established in pediatric patients.
Category D. (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)
It is not known whether pralatrexate is distributed into human milk. Because of the potential for serious adverse reactions to pralatrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.
In the PROPEL study, 36% of patients were 65 years of age and older. Although no overall differences in safety and efficacy were observed in geriatric patients, some data indicate that geriatric patients (65 years of age and older) may be at increased risk of developing mucositis compared with younger adults. (See Mucositis under Cautions: Warnings/Precautions.) While the manufacturer states that no dosage adjustment is required in geriatric patients with normal renal function, it should be noted that age-related decline in renal function may result in reduced clearance of and increased exposure to pralatrexate.
ICD codes
No ICD codes are available for this drug.
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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