AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• PRALAtrexate

Chemical Name:

• (2 S )-2[[4-[1 RS )-1-[2,4-diaminopteridin-6-yl)methyl]but-3-ynyl]benzoyl]amino]pentanedioic acid

Molecular Formula:

• C₂₃H₂₃N₇O₅

Pralatrexate, a folic acid antagonist, is an antineoplastic agent.1,  3,  4,  5,  6,  7,  8,  9

Peripheral T-cell Lymphoma

Pralatrexate is used for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL)1,  2 and is designated an orphan drug by the US Food and Drug Administration (FDA) for use in this condition.2 The current indication for pralatrexate is based on overall response rate; clinical benefit (e.g., improvement in progression-free or overall survival) has not been established.1

The current indication for pralatrexate is based principally on the results of a phase 2, open-label, single-arm, multicenter study (PROPEL) in 109 evaluable patients 21-85 years of age (median age: 59 years) with relapsed or refractory peripheral T-cell lymphoma who had received at least one prior treatment.1,  3 Patients enrolled in this study had received a median of 3 prior treatments; 63% of patients did not have evidence of response to their most recent treatment prior to study entry, and 24% of patients did not have evidence of response to any previous treatments.1,  3 In this study, patients received pralatrexate (30 mg/m² administered by rapid IV injection over 3-5 minutes) once weekly for 6 weeks, followed by one week of rest;1,  3 this 7-week cycle was continued until disease progression or unacceptable toxicity occurred.1 Response and disease progression, assessed at the end of cycle 1 and then every 14 weeks thereafter, were evaluated by independent central review using the International Workshop Criteria (IWC).1,  3 Treatment with pralatrexate resulted in an overall response rate (complete and partial responses) of 27%.1,  3 Approximately 66% of responses occurred during the first cycle of treatment; the median time to first response was 45 days.1 The median duration of response reportedly was 9.4 months;1,  12 however, this estimate for duration of response may not be accurate since the long interval (14 weeks) between efficacy assessments and the lack of subsequent assessments in some patients make it difficult to determine the actual time when a response or progression occurred.12 Because of these study limitations, durable response (response lasting at least 14 weeks and confirmed by subsequent assessments) was considered by some clinicians to be a preferred efficacy parameter over duration of response; durable response was achieved in 12% of patients receiving pralatrexate.12

General

Pralatrexate should be administered under the supervision of a qualified clinician experienced in the use of antineoplastic agents.1 In addition, adequate diagnostic and treatment facilities must be readily available for appropriate management of complications.1

All patients should be instructed to take a low dose (1-1.25 mg) of oral folic acid daily to reduce toxicity.1 Folic acid should be initiated 10 days prior to the first dose of pralatrexate; folic acid should be continued during the full course of therapy and for 30 days after the last dose of pralatrexate.1 Patients also should receive an IM injection of vitamin B₁₂ (1 mg) no more than 10 weeks prior to the first dose of pralatrexate and every 8-10 weeks thereafter; injections administered subsequent to the initial dose may be given on the same day as pralatrexate.1

Complete blood cell counts (CBCs) and severity of mucositis and other treatment-related toxicities (e.g., hepatotoxicity) should be assessed weekly during therapy (i.e., just prior to each dose).1 Prior to administering any dose of pralatrexate, mucositis should be grade 1 or lower, platelet counts should be at least 100,000/mm³ (prior to the first dose) or at least 50,000/mm³ (prior to subsequent doses), and absolute neutrophil counts (ANCs) should be at least 1000/mm³.1 Serum chemistry tests, including hepatic and renal function tests, should be performed before administration of the first and fourth pralatrexate doses of each treatment cycle.1 (See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)

Administration

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.1

The usual precautions for handling, preparing, and administering solutions of cytotoxic drugs should be observed with pralatrexate.1 The manufacturer recommends use of gloves and other protective clothing when handling the drug.1 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.1

The appropriate volume of pralatrexate 20-mg/mL injection should be aseptically withdrawn into a syringe for immediate use.1 Pralatrexate injection should not be diluted.1 Because pralatrexate injection contains no preservatives, any unused portions should be discarded.1

Pralatrexate injection should be stored in the original carton at 2-8°C and protected from light until use.1 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.1

Dosage

Peripheral T-cell Lymphoma

The recommended adult dosage of pralatrexate for the treatment of relapsed or refractory peripheral T-cell lymphoma is 30 mg/m² (administered by rapid IV injection over 3-5 minutes) once weekly for 6 weeks, followed by one week of rest;1 this 7-week cycle should be continued until disease progression or toxicity occurs.1 In the phase 2, open-label, single-arm, multicenter study (PROPEL), pralatrexate was administered for a median of 70 days.1

CBCs and severity of mucositis and other treatment-related toxicities (e.g., hepatotoxicity) should be assessed weekly during therapy (i.e., just prior to each dose).1 Prior to administering any subsequent doses of pralatrexate, mucositis should be grade 1 or lower, platelet counts should be at least 50,000/mm³, and ANCs should be at least 1000/mm³.1 (See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)

Dosage Modification for Toxicity

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.1 Depending on the severity of the toxicity, subsequent doses of pralatrexate may be omitted and/or reduced, or pralatrexate therapy may be discontinued permanently.1,  11 (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.1

Special Populations

Dosage reductions other than those recommended for all patients are not needed in geriatric patients (65 years of age and older) who have normal renal function.1

Contraindications

The manufacturer states that there are no known contraindications to the use of pralatrexate.1

Warnings/Precautions

Hematologic Toxicity

The principal manifestations of hematologic toxicity include thrombocytopenia, anemia, and neutropenia.1 In the phase 2, open-label, single-arm, multicenter study (PROPEL), thrombocytopenia, anemia, and neutropenia were reported in 41, 34, and 24%, respectively, of patients receiving pralatrexate.1 Dosage of pralatrexate should be adjusted based on the absolute neutrophil count (ANC) and platelet count just prior to each dose (i.e., determined on day of treatment).1 (See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)

Mucositis

Mucositis1,  3,  4,  5 (i.e., stomatitis or mucosal inflammation of the GI and genitourinary tracts) was reported in 70% of patients receiving pralatrexate in the PROPEL study.1 Mucositis typically occurs within 2-5 days after initiation of pralatrexate.11 In the PROPEL study, grade 3 or 4 mucositis occurred in 17 or 4% of patients, respectively,1 with a median time to onset of 15 days and a median duration of 13 days.11

In several analyses of patients receiving pralatrexate, the severity of mucositis appeared to be related to higher baseline concentrations of methylmalonic acid (MMA, a marker of vitamin B deficiency6 ) or higher systemic exposure (i.e., area under the plasma concentration-time curve [AUC]) to pralatrexate.5,  11 Mucositis also appeared to occur somewhat more frequently in geriatric patients (65 years of age and older) than in younger adults.11

To reduce pralatrexate-induced mucositis, the manufacturer recommends supplementation with folic acid and vitamin B₁₂ before and during therapy with pralatrexate.1 (See Dosage and Administration: General.) The manufacturer and the National Comprehensive Cancer Network (NCCN) also recommend other strategies to prevent oral mucositis, including maintaining fluid and protein intake, establishing an effective oral hygiene protocol, using topical therapies (e.g., oral cryotherapy when feasible), and avoiding irritants (e.g., alcohol or alcohol-containing medications, tobacco, specific foods).11,  14

If mucositis occurs during pralatrexate therapy, pain may be relieved by altering eating and drinking habits, using topical anesthetics (e.g., “magic mouthwash”), and/or using systemic (e.g., opiate) analgesics.11 The manufacturer's labeling and/or published guidelines should be consulted for specific recommendations on the management of mucositis.11,  14 If mucositis is grade 2 or higher, subsequent doses of pralatrexate should be omitted and/or reduced, or pralatrexate therapy discontinued permanently.1,  11 (See Dosage Modification for Toxicity under Dosage and Administration: Dosage.)

Folate and Vitamin B12 Supplementation

Patients must receive folic acid and vitamin B₁₂ to prevent treatment-related hematologic and GI toxicity (i.e., mucositis).1,  5 (See Dosage and Administration: General.) Administration of supplemental folic acid and vitamin B₁₂ has been shown to normalize MMA concentrations and reduce the severity of GI toxicity.5

Fetal/Neonatal Morbidity and Mortality

Pralatrexate may cause fetal harm; embryotoxicity, fetotoxicity, and fetal lethality have been demonstrated in animals.1 Pregnancy should be avoided during therapy.1 If used during pregnancy or if the patient becomes pregnant while receiving pralatrexate, the patient should be apprised of the potential fetal hazard.1

Hepatotoxicity

Elevations in serum aminotransferase (transaminase) concentrations (i.e., AST [SGOT], ALT [SGPT]) have been reported with pralatrexate.1 Persistent abnormalities in liver function test results may indicate hepatotoxicity.1 Liver function tests should be performed before administration of the first and fourth pralatrexate doses of each treatment cycle.1 If hepatotoxicity is grade 3 or higher, subsequent doses of pralatrexate should be omitted and/or reduced, or pralatrexate therapy discontinued permanently.1,  11 (See Table 3.)

Adequate Patient Evaluation and Monitoring

Pralatrexate should be administered under the supervision of qualified clinicians experienced in the use of cytotoxic therapy.1

Complete blood cell counts (CBCs), including platelet counts and ANCs, should be obtained prior to initiation of pralatrexate therapy and monitored weekly during therapy (i.e., just prior to each dose).1 Severity of mucositis should be assessed prior to each scheduled dose of pralatrexate.1 In addition, serum chemistry tests, including hepatic and renal function tests, should be performed before administration of the first and fourth pralatrexate doses of each treatment cycle.1

Specific Populations

Pregnancy

Category D.1 (See Users Guide.) (See Fetal/Neonatal Morbidity and Mortality under Cautions: Warnings/Precautions.)

Lactation

It is not known whether pralatrexate is distributed into human milk.1 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.1

Pediatric Use

Safety and efficacy of pralatrexate have not been established in pediatric patients.1

Geriatric Use

In the PROPEL study, 36% of patients were 65 years of age and older.1 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.11 (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.1

Hepatic Impairment

Safety and efficacy of pralatrexate have not been established in patients with hepatic impairment.1 Patients were excluded from the pralatrexate lymphoma clinical trials if their total bilirubin concentrations exceeded 1.5 mg/dL and their AST (SGOT) or ALT (SGPT) concentrations were more than 2.5 times the upper limit of normal (or more than 5 times the upper limit of normal if there was documented hepatic involvement with the lymphoma).1

Renal Impairment

Safety and efficacy of pralatrexate have not been established in patients with renal impairment; however, data from a population pharmacokinetic analysis indicate that drug clearance decreases with declining creatinine clearance.1 Pralatrexate should be used with caution in patients with moderate or severe renal impairment.1

Common Adverse Effects

The most common adverse effects of pralatrexate include mucositis,1 thrombocytopenia,1,  3,  4 nausea,1 and fatigue.1 Other common adverse effects reported in more than 20% of patients include anemia,1 constipation,1 pyrexia,1 edema,1 cough,1 epistaxis,1 vomiting,1 neutropenia,1 and diarrhea.1 The most common serious adverse effects of pralatrexate include pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia.1

No formal drug interaction studies have been performed to date.1

In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of cytochrome P-450 (CYP) isoenzymes.1 Pralatrexate also is not a substrate or inhibitor of the P-glycoprotein transport system.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely with drugs affecting or metabolized by CYP isoenzymes.1

Drugs Eliminated by Renal Excretion

Possible pharmacokinetic interaction (delayed clearance of pralatrexate) with drugs that undergo substantial renal excretion (e.g., co-trimoxazole, nonsteroidal anti-inflammatory agents [NSAIAs]).1

Probenecid

Pharmacokinetic interaction (delayed clearance of and increased exposure to pralatrexate).1

Description

Pralatrexate, a 10-deazaaminopterin analog of methotrexate, is an antineoplastic agent.1,  4,  5,  6,  7,  8,  9 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.7,  8 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).4,  5,  6,  7,  8,  10,  11 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.6,  7,  8,  11 Like methotrexate, polyglutamylated pralatrexate exerts its antineoplastic activity by disrupting folate-dependent metabolic processes that are essential for cell replication.11 Specifically, pralatrexate inhibits dihydrofolate reductase (DHFR), an enzyme involved in the synthesis of deoxythymidine and purine nucleotides.1,  6,  8,  11 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).11,  12

In preclinical studies, pralatrexate demonstrated greater affinity for RFC-1 (resulting in enhanced intracellular transport),4 enhanced polyglutamylation (resulting in increased intracellular drug retention and accumulation), and improved cytotoxicity compared with other folic acid antagonists (e.g., methotrexate, pemetrexed).6,  7,  8,  9,  10,  11 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.8,  15

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.1 In vitro studies indicate that pralatrexate is approximately 67% bound to plasma proteins.1 Following multiple treatment cycles, no accumulation of pralatrexate was observed.1 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.1 In vitro studies indicate that pralatrexate is not a substrate or inhibitor of the P-glycoprotein transport system.1 The terminal elimination half-life of pralatrexate is 12-18 hours.1 Following a single rapid IV injection of pralatrexate (30 mg/m² over 3-5 minutes), approximately 34% of pralatrexate is excreted unchanged in urine.1 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.1 In a population pharmacokinetic analysis, drug clearance decreased with decreasing creatinine clearance.1 There was no substantial effect of gender on pharmacokinetics of pralatrexate.1

Advice to Patients

Importance of taking folic acid and vitamin B₁₂ to reduce the risk of adverse effects.1,  13

Risk of mucositis.1 Importance of immediately informing clinicians of redness and/or soreness in the mucous membranes, including the mouth, lips, throat, and other areas along the GI tract and genital areas.11,  13 Importance of understanding measures to prevent mucositis and to minimize discomfort should it occur.1,  13 (See Mucositis under Cautions: Warnings/Precautions.)

Risk of thrombocytopenia, anemia, and neutropenia.1 Importance of reporting any unusual bleeding (e.g., nosebleed), bruising, weakness, fatigue, pallor, shortness of breath, or fever or other manifestations of infection (e.g., chills, cough, pain or burning upon urination).13

Necessity of obtaining complete blood cell counts (CBCs) as well as renal and liver function tests periodically.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,  13 Apprise patient of potential hazard to the fetus if used during pregnancy; women of childbearing potential should avoid becoming pregnant.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., co-trimoxazole, probenecid) and OTC drugs (e.g., nonsteroidal anti-inflammatory agents [NSAIAs]), as well as any concomitant illnesses.1,  13

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Allos Therapeutics, Inc. Folotyn^® (pralatrexate) injection prescribing information. Westminster, CO; 2009 Sep.

2. Food and Drug Administration. Orphan designation pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act. (P.L. 97-414). Rockville, MD; From FDA website; accessed 2009 Nov 3. [Web]

3. O'Connor O, Pro B, Pinter-Brown L et al. PROPEL: Results of the pivotal, multicenter, phase II study of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). J Clin Oncol . 2009; 17(suppl): Abstract 8561 (presented at the 45th Annual ASCO meeting. Orlando, FL: 2009 May 29.

4. O'Connor OA, Horwitz S, Hamlin P et al. Phase II-I-II study of two different doses and schedules of pralatrexate, a high-affinity substrate for the reduced folate carrier, in patients with relapsed or refractory lymphoma reveals marked activity in T-cell malignancies. J Clin Oncol . 2009; 27:4357-64. [PubMedCentral][PubMed 19652067]

5. Mould DR, Sweeney K, Duffull SB et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther . 2009; 86:190-6. [PubMed 19474785]

6. Molina JR. Pralatrexate, a dihydrofolate reductase inhibitor for the potential treatment of several malignancies. IDrugs . 2008; 11:508-21. [PubMed 18600598]

7. Kisliuk RL. Deaza analogs of folic acid as antitumor agents. Curr Pharm Des . 2003; 9:2615-25. [PubMed 14529545]

8. Izbicka E, Diaz A, Streeper R 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; 64:993-9. [PubMedCentral][PubMed 19221750]

9. Wang ES, O'Connor O, She Y et al. Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Leuk Lymphoma . 2003; 44:1027-35. [PubMed 12854905]

10. O'Connor OA, Hamlin PA, Portlock C et al. Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. Br J Haematol . 2007; 139:425-8. [PubMed 17910632]

11. Allos Therapeutics, Inc., Westminster, CO: Personal communication.

12. Justice RL. Pralatrexate: FDA approval package. NDA number: 22-468. Rockville, MD: US Food and Drug Administration. From FDA website. Accessed 2010 Jan 28. [Web]

13. Allos Therapeutics, Inc. Folotyn^® (pralatrexate) injection patient information. Westminster, CO. Accessed 2010 Feb 4.

14. Bensinger W, Schubert M, Ang KK et al. NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw . 2008; 6 Suppl 1:S1-21. [PubMed 18289497]

15. Mauritz R, Peters GJ, Priest DG et al. Multiple mechanisms of resistance to methotrexate and novel antifolates in human CCRF-CEM leukemia cells and their implications for folate homeostasis. Biochem Pharmacol . 2002; 63:105-15. [PubMed 11841783]