Pemetrexed, a Novel Antifolate Therapeutic Alternative for Cancer Chemotherapy

Leticia R. Villela, Pharm.D.; Brad L. Stanford, Pharm.D.; Sachin R. Shah, Pharm.D.

Disclosures

Pharmacotherapy. 2006;26(5):641-654. 

In This Article

Abstract and Introduction

Abstract

Pemetrexed is a newly approved antifolate agent for the treatment of malignant pleural mesothelioma (MPM) and metastatic non-small cell lung cancer (NSCLC). We performed a PubMed/MEDLINE database search to identify relevant literature from January 19662005. Bibliographies from identified references were searched as well, as were abstracts from the 2004 and 2005 proceedings of the American Society of Clinical Oncology. We discuss the pharmacology of pemetrexed, describing its mechanism of action and comparing it with methotrexate. The pharmacokinetics and pharmacodynamics of pemetrexed are described to provide a better understanding of the properties of this drug. Therapeutic uses are assessed, beginning with the approved indications of MPM and NSCLC. However, pemetrexed has been studied in numerous phase II trials for other types of solid malignancies, and completed trials are reviewed. Data on adverse effects and drug interactions are also provided. Finally, dosing and administration are reviewed, including appropriate premedication. Premedication, including administration of steroids and vitamin supplements, has been shown to decrease the frequency and severity of pemetrexed toxicities. Pemetrexed should be used as a standard of care for unresectable MPM and recurrent metastatic NSCLC.

Introduction

Antifolates are antineoplastic agents that have been used to treat many solid tumors and hematologic malignancies. Folic acid antagonists (aminopterin and, later, methotrexate) were first used in the late 1940s.[1] Folic acid antagonists produced the first remissions in leukemia, as well as the first cure for choriocarcinoma.[2,3] Since that discovery, methotrexate has been used to treat various oncologic disorders, including leukemia, lymphoma, breast cancer, colorectal cancer, head and neck cancer, osteogenic sarcoma, urothelial cancer, and choriocarcinoma.[4]

Folic acid is essential for the synthesis of DNA and RNA precursors and for the synthesis of thymidine nucleotide that is incorporated exclusively into DNA.[5] Folic acid in its fully reduced form serves as a one-carbon carrier required for the synthesis of thymidylate, purine nucleotides, and certain amino acids. Normal cells, as well as tumor cells, use the pool of active reduced folate to proliferate. The cytotoxic activity of antifolates in particular is mainly due to their ability to inhibit several different folate-dependent enzymes involved in DNA synthesis. Folate antagonists that have proved successful in various oncologic disorders include fluorouracil, capecitabine (the oral prodrug of fluorouracil), and methotrexate. Fluorouracil specifically inhibits thymidylate synthase, whereas methotrexate is a potent inhibitor of dihydrofolate reductase (DHFR).

Since the introduction of methotrexate, no new approved DHFR inhibitor had been introduced that could be used for malignancies, until the development of pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN). Pemetrexed is a novel antifolate that inhibits multiple enzymes involved in the synthesis of nucleotides, ultimately hindering RNA and DNA synthesis. This is the only drug, in combination with cisplatin, that has shown promise in the treatment of malignant pleural mesothelioma (MPM). In February 2004, the United States Food and Drug Administration (FDA) approved pemetrexed for the treatment of MPM and 6 months later for non-small cell lung cancer (NSCLC). We performed a PubMed/MEDLINE database search to identify relevant literature from January 1966-April 2005. Bibliographies from identified references were searched as well, as were abstracts from the 2004 and 2005 proceedings of the American Society of Clinical Oncology. We reviewed the phase III trials in which pemetrexed acquired FDA indications and some phase II trials. Information regarding pharmacokinetics, adverse effects, and dosing is also reviewed.

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