Kidney tubular toxicity of maintenance pemetrexed therapy featuring kenar jhaveri, md, eajkd blog editor and authors. Based on its mechanism of action, alimta can cause fetal harm when administered to a pregnant woman. Pemetrexed is a pyrrolopyrimidine antifolate that exerts its antineoplastic activity by inhibiting thymidylate synthase ts, glycinamide ribonucleotide formyltransferase garft. Jun 03, 2019 alimta pemetrexed for injection, for intravenous use. Pharmacology and mechanism of action of pemetrexed clinical. Coadministration with ibuprofen, an oat3 inhibitor, decreased the clearance and increased the auc of pemetrexed by approximately 20% in patients with normal renal function crcl greater than 80 mlmin.
In females of reproductive potential, verify pregnancy status prior to initiating keytruda and advise them to use effective contraception during treatment and for 4 months after the last dose. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Mechanism of action of anthracycline drugs baoxu pang and colleagues report a novel mechanism of action of doxorubicin and other anthracycline drugsthe induction of histone. Pharmacology and mechanism of action of pemetrexed. The role of pemetrexed in advanced non smallcell lung. Based on its mechanism of action, keytruda can cause fetal harm when administered to a pregnant woman. Mechanism of action of anthracycline drugs baoxu pang and colleagues report a novel mechanism of action of doxorubicin and other anthracycline drugsthe induction of histone eviction. Pemetrexed is a folate analog inhibitor antifolate that disrupts folatedependent metabolic processes essential for cell replication. Alkylating agent special pediatric considerations are noted when applicable, otherwise adult provisions apply. In vitro, pemetrexed is a substrate of organic anion transporter 3 oat3 and 4 oat4. Carboplatin is a derivative of cisplatin and has a similar mechanism of action, differing only in terms of structure and toxicity. Aug 21, 2019 based on findings from animal studies and its mechanism of action, alimta can cause fetal harm when administered to a pregnant woman. Randomized phase iii trial of pemetrexed versus docetaxel in. Pdf pemetrexed is a newer antifolate drug that has been approved as firstline.
Structural basis of methotrexate and pemetrexed action on. Mechanism of action pemetrexed for injection, is a folate analog metabolic inhibitor that exerts its action by disrupting folatedependent metabolic processes essential for cell replication. Discuss the rationale for the fda approval of pemetrexed. Pdf the role of pemetrexed in advanced non smallcell. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as. Therapeutic uses are assessed, beginning with the approved indications of mpm and nsclc. In animal reproduction studies, intravenous administration of pemetrexed to pregnant mice during the period of organogenesis was teratogenic, resulting in developmental delays and increased malformations at doses. Mechanism of action of keytruda pembrolizumab health. Pemetrexed is not metabolized to an appreciable extent.
Carcinogenesis, mutagenesis, impairment of fertility. Carboplatin and pemetrexed with or without pembrolizumab. Pemetrexed is a newgeneration antifolate, approved for the treatment of mesothelioma and nonsmall cell lung cancer, currently being evaluated for the treatment of a variety of other solid tumors. Based on findings from animal studies and its mechanism of action, alimta can cause fetal harm when administered to a pregnant woman. Currently, lung cancer has remained the most common cause of cancer death while nonsmall cell lung cancer nsclc accounts for the most of all lung cancer cases. Combination of pembrolizumab, carboplatin, and pemetrexed could be an effective and tolerable firstline treatment option for patients with advanced nonsquamous nsclc. Pemetrexed also inhibits dihydrofolate reductase dhfr and glycinamide ribonucleotide formyltransferase garft, which are key enzymes required for the. Pemetrexed alimta,elilillyandcompany,indianapolis, in is a novel, multitargeted antifolate chemotherapy agent that is active in multiple tumor types including nsclc. Pemetrexed is a newer antifolate drug that has been approved as firstline treatment for patients with advanced nonsquamous, nonsmall cell lung cancer nsclc in combination with cisplatin, and as single agent for relapsed or chemotherapy refractory nsclc after platinumcontaining chemotherapy, at a dose of 500 mgm2. Mechanism of action pemetrexed is a multitargeted antifolate drug that targets the enzymes thymidylate synthase ts, dihydrofolate reductase dhfr, and glycinamide ribonucleotide. Its indications are the treatment of pleural mesothelioma and nonsmall cell lung cancer nsclc. Pemetrexed is a newgeneration antifolate, approved for the treatment of mesothelioma and nonsmall cell lung cancer, currently being evaluated for the treatment of a. It represents a challenge for oncologist, as the current treatment options are noncurative in the. Molecular mechanism implicated in pemetrexedinduced.
Pemetrexed brand name alimta is a chemotherapy drug manufactured and marketed by eli lilly and company. This action also effects normal cells which can cause significant side effects in the body, such as low blood cell counts, nausea, and vomiting. The compounds are divided into p, b, and emoieties, as referenced throughout the text. The role of pemetrexed in advanced non smallcell lung cancer. It is indicated for use in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for curative surgery. In addition, pemetrexed inhibits dhfr as well as garft which is a folatedependent enzyme involved in purine synthesis fig. Several payment sources exist for cancer drugs in ontario, depending.
The pharmacokinetics and pharmacodynamics of pemetrexed are. Evidence of pemetrexeds multitargeted mechanism of action is the ability of leucovorin and thymidine to circumvent the cytotoxic action in the human ccrf. The understanding of the mechanism of methotrexate action and its selectivity was broadened. In february 2004, the food and drug administration approved pemetrexed for treatment of malignant pleural mesothelioma, a type of tumor of the. Pemetrexed, a novel antifolate therapeutic alternative for. Pemetrexed is classified as an antifolate antimetabolite. Pemetrexed is a novel multitargeted antifolate that inhibits. The concomitant administration of pemetrexed with nsaids or aspirin at higher dose should be avoided for 2 days before, on the day of, and 2 days following pemetrexed administration on patients with mild to. We discuss the pharmacology of pemetrexed, describing its mechanism of action and comparing it with methotrexate. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1833rd the recommended human dose.
The recommended dose of alimtafor treatment of recurrent nonsquamous nsclcinpatients with a creatinine clearance calculated by cockcroftgault equation of 45mlmin or greateris. Pemetrexed pharmacokinetics and pharmacodynamics in a phase i. Special focus on pharmacology and mechanism of action. Mechanisms of resistance to pemetrexed in nonsmall cell. The anticancer activity of cisplatin was discovered in the early.
It was approved by the fda in the 1980s and since then it has been. Phase ii study of pemetrexed in breast cancer patients pretreated. Access and take the cme test online and receive 1 hour of ama pra category 1 credit at cme. The concomitant administration of pemetrexed with nsaids or aspirin at higher dose. Like 5fluorouracil and raltitrexed, pemetrexed primarily inhibits thymidylate synthase ts resulting in decreased. Tumors with codeletion of the methylthioadenosine phosphorylase gene, as a consequence of p16 deletions, may be particularly sensitive to pemetrexed. Based on its mechanism of action, pemetrexed for injection can cause fetal harm when administered to a pregnant woman.
Pemetrexed eli lilly and company next previous table of contents at a glance. Pemetrexed pharmacokinetics and pharmacodynamics in a. A link to download a pdf version of the drug profile will be included in your email receipt. Antimetabolites, mucositis, multitargeted antifolate, myelosuppression, vitamin supplementation pharmacology and. Based on findings in animal reproduction studies and on the mechanism of action, pemetrexed may cause fetal harm if administered to a pregnant female. Pemetrexed fda prescribing information, side effects and. The discordance between response rate and pfs was attributed to chance imbalances within this small. Alimta pemetrexed for injection is a folate analog metabolic inhibitor. Highlights of prescribing information history of severe. An efficient synthesis of pemetrexed disodium qi 2015. Pemetrexed pharmacokinetics and pharmacodynamics in a phase iii study of doublet chemotherapy with vinorelbine. Pemetrexed is a novel multitargeted antifolate that inhibits or 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis. If you are allergic to pemetrexed, tell your doctor because you should not receive it.
Mechanism of action pathway of tetrahydrofolate and antimetabolites pemetrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. Alimta pemetrexed disodium injection, powder, lyophilized, for solution for intravenous use. An efficient synthetic method for the pemetrexed disodium has been developed using methyl 4. Dec 03, 2019 based on findings in animal reproduction studies and on the mechanism of action, pemetrexed may cause fetal harm if administered to a pregnant female. The pharmacokinetics and pharmacodynamics of pemetrexed are described to provide a better understanding of the properties of this drug. For treating certain cancers such as a type of lung cancer called nonsmall cell lung cancer and a type of cancer inside the lining of the chest cavity called mesothelioma. Alimta, pemetrexed for injection, is a whitetolight yellow or greenyellow lyophilized powder supplied in singledose vials for reconstitution for intravenous infusion. Metastatic melanoma is a lethal skin cancer and its incidence is rising every year. Randomized phase iii trial of pemetrexed versus docetaxel. Pharmacology and mechanism of action of pemetrexed request pdf. Mechanism of action pemetrexed is a multitargeted antifolate drug that targets the enzymes thymidylate synthase ts, dihydrofolate reductase dhfr, and glycinamide ribonucleotide formyl transferase garft 8. The drug substance, pemetrexed disodium heptahydrate, has the chemical name lglutamic acid, n422amino4,7dihydro4oxo1hpyrrolo2,3dpyrimidin5ylethylbenzoyl, disodium salt, heptahydrate with a molecular formula of c 20 h 19 n 5 na 2 o. In an exploratory comparison between volasertib monotherapy and pemetrexed monotherapy, the hr was 2. Oct 05, 2014 cisplatin is stable under normal temperatures and pressures, but may transform slowly over time to the transisomer iarc 1981, akron 2009.
Pemetrexed exerts its chemotherapeutic effect by disrupting production of folate which is essential for cell replication. The overall yield of pemetrexed disodium was increased from 12. Request pdf pharmacology and mechanism of action of pemetrexed pemetrexed is a novel multitargeted antifolate that inhibits or 3 enzymes involved in folate metabolism and purine. Structural basis of methotrexate and pemetrexed action on serine hydroxymethyltransferases revealed using plant models. Alimta pemetrexed disodium dose, indications, adverse.
Explain the mechanism of action of a recently approved new cancer drug, pemetrexed. Request pdf pharmacology and mechanism of action of pemetrexed pemetrexed is a novel multitargeted antifolate that inhibits or 3 enzymes involved in folate metabolism and purine and. The anticancer activity of cisplatin was discovered in the early 1960s by professor barnett rosenberg at the university of michigan rosenberg, vancamp, krigas, 1965. Pdf the role of pemetrexed in advanced non smallcell lung. Like 5fluorouracil and raltitrexed, pemetrexed primarily inhibits thymidylate synthase ts resulting in decreased thymidine available for dna synthesis. Ts converts deoxyuridine monophosphate to deoxythymidine monophosphate during pyrimidine synthesis, garft is involved in purine synthe. Pemetrexed fda prescribing information, side effects and uses. B mechanism of action and pharmacokinetics pemetrexed is a pyrrolopyrimidine antifolate that exerts its antineoplastic activity by inhibiting thymidylate synthase ts, glycinamide ribonucleotide formyltransferase garft and dihydrofolate reductase dhfr, which are involved in folate metabolism and dna synthesis, resulting in inhibition of.
More important, vitamin supplementation has not been shown to adversely affect efficacy in some tumor types. Pemetrexed is a chemotherapy drug that is manufactured and marketed by eli lilly and company under the brand name alimta. It was approved by the fda in the 1980s and since then it has been widely used. Pemetrexed is a newer antifolate drug that has been approved as firstline treatment for patients with advanced nonsquamous, nonsmall cell lung cancer nsclc in combination. Dec 23, 2019 structural formulas of tetrahydrofolate thf, methotrexate mtx, and pemetrexed ptx. Mechanism of action and pharmacokinetics indications and status adverse effects dosing administration guidelines special precautions interactions recommended clinical monitoring.
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