Pemetrexed Disodium

Description

Pemetrexed, a pyrrolo[2,3-d]pyrimidine-based antifolate that disrupts cell replication by inhibiting multiple folate-dependent metabolic processes, was initially developed and launched in the US for the treatment of malignant pleural mesothelioma in conjunction with cisplatin. Patients who are not candidates for surgery may benefit from this combination therapy. Clinical data demonstrated that the median overall survival time increased to 12.1 months, compared with 9.3 months for patients receiving cisplatin alone. In August of 2004, the FDA also approved pemetrexed as a second-line treatment of non-small-cell lung cancer (NSCLC). While median survival is comparable to the standard second-line treatment docetaxel, the improved toxicity profile (significant reduction in neutropenia) accelerated the approval for NSCLC. Its effectiveness as an anticancer drug is derived from its ability to gain internal cell access via the reduced folate carrier and membrane folate binding protein transport systems. Once inside, pemetrexed undergoes polyglutamation, and the resultant polyglutamate forms (predominantly the pentaglutamate) inhibit the folate-dependent enzymes thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). Against recombinant human TS, pemetrexed has a Ki of 109nM while the triglutamate and pentaglutamate forms have Ki values of 1.6nM and 1.3 nM, respectively. All forms of pemetrexed display similar potency against recombinant human DHFR (7 nM), but the pentaglutamate form is significantly more potent against recombinant murine GARFT than the parent (Ki=65nM versus 9.3μM). The selectivity of pemetrexed may be explained by the fact that polyglutamation is more likely to occur in cancer cells compared to normal cells while its prolonged duration of action may be attributed to decreased cellular efflux of the polyglutamate forms. While several different routes have provided pemetrexed, one of the most efficient exploits the propensity of 2,6-diamino-3Hpyrimidin- 4-one to undergo Michael additions at its unsubstituted C-5 position. Using ethyl 4-(4-nitrobut-3-enyl)benzoate as the Michael acceptor, the resulting adduct is then converted to the ultimate precursor for glutamyl coupling via a onepot, three-step process (Nef reaction to transform the nitro to the aldehyde, intramolecular condensation to afford the pyrrole, and saponification of the ethyl ester). A typical treatment regimen involves intravenous administration of pemetrexed, infused over ten minutes, at a dose of 500mg/m2 followed by a thirty minute wash-out period and then cisplatin intravenously over two hours at a dose of 75mg/m². Both drugs are given on Day 1 of a 21-day cycle. In order to reduce treatment-related hematological and GI toxicity, patients are instructed to take folic acid and vitamin B₁₂ as a prophylactic measure. Pretreatment with a corticosteroid is also recommended to prevent possible skin rashes. Pemetrexed is primarily excreted intact in the urine, with 70–90% of the dose being recovered within 24 hours of administration. The half-life of pemetrexed is 3.5 hours in patients with normal renal function, and the total systemic clearance is 91.8mL/min. As expected, clearance decreases as renal impairment increases. The drug’s plasma protein binding is 81%, and it has a steady state volume of distribution of 16.1 L. The pharmacokinetics of pemetrexed is linear with dose and remains unchanged over multiple treatment cycles. While in vitro studies suggest that pemetrexed would not interfere with drugs metabolized by CYP3A4, CYP2D6, CYP2C9, and CYP1A2, ibuprofen (400mg q.d.) does reduce pemetrexed clearance by 20%. Caution should, therefore, be taken when administering pemetrexed concurrently with ibuprofen to patients with renal insufficiency and should not be given at all to patients whose creatinine clearance is ＜45mL/min. .

Chemical properties

Crystalline Solid

Originator

Eli Lilly (US)

The Uses of Pemetrexed Disodium

Multitargeted antifolate; inhibits thymidylate synthase as well as other folate dependent enzymes. Antineoplastic

The Uses of Pemetrexed Disodium

Pemetrexed is a novel antifolate and antimetabolite for TS, DHFR and GARFT with Ki of 1.3 nM, 7.2 nM and 65 nM, respectively

The Uses of Pemetrexed Disodium

Multitargeted antifolate; inhibits thymidylate synthase as well as other folate dependent enzymes. Antineoplastic.

What are the applications of Application

Pemetrexed Disodium is a novel multitargeted antifolate antineoplastic agent and inhibitor of TS, DHFR and GARFT.

Definition

ChEBI: An organic sodium salt that is the disodium salt of N-{4-[2-(2-amino-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid. Inhibits thymidylate synthase (TS), 4 1 dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT).

brand name

Alimta (Lilly).

General Description

The drug is available in a 100-mg sterile vial for IV use. Thedrug appears to be effective against a range of tumors includingmesothelioma, NSCLC, colorectal cancer, bladdercancer, and lung cancer. The mechanism of action involvesinhibition of TS resulting in inhibition of thymidylate andDNA synthesis. This drug is a pyrrolopyrimidine analog offolate with antifolate activity. Resistance can occur by increasedexpression of TS, decreased binding affinity for TS,or decreased drug transport into cells. The drug is administeredonly via the IV route and distributes to all tissues.Cellular activation to the more potent polyglutamated formsoccurs, and the majority of the dose is excreted unchangedin the urine. The drug interaction and toxicity profiles aresimilar to that of methotrexate.

Mechanism of action

Like methotrexate, it is actively transported into tumor cells through reduced folate carriers and, in polyglutamated form, inhibits the synthesis of pyrimidine and purine-based nucletotides by disrupting folatedependent metabolic processes . In addition to DHFR, this pyrrolopyrimidine-based inhibitor binds tightly to thymidylate synthase and GAR transformylase.

Clinical Use

Pemetrexed is a novel multitarget antifolate used by the IV route for the treatment of advanced or metastatic nonsmall cell lung cancer and in combination with cisplatin in malignant pleural mesothelioma.

Side Effects

Patients on pemetrexed must take folate and vitamin B12 supplements to reduce the risk of bone marrow suppression (neutropenia, thrombocytopenia, and anemia) and GI side effects. Pretreatment with corticosteroids can reduce the risk of drug-induced skin rash. Pemetrexed has a half-life of 3.5 hours and is excreted primarily unchanged via the kidneys. Significant cross-resistance has been noted between pemetrexed and other pyrimidine and folate antagonists.

Synthesis

A number of papers outlining the syntheses of pemetrexed and related analogs have appeared. A practical and scalable synthetic route is depicted in Scheme 9. Palladium (0) coupling of methyl 4-bromobenzoate (57) with 3-butyn-1-ol (58) gave crystalline 59, which was then reduced over palladium on carbon in DCM to give alcohol 60. Filtration of the catalyst afforded a DCM solution of alcohol 60, which was utilized directly in a TEMPO-catalyzed sodium hypochlorite oxidation, providing known aldehyde 61 without isolation. Addition of 5,5-dibromobarbituric acid (DBBA) and catalytic amount of HBr in acetic acid to the DCM solution of 61 effected the conversion to a-bromoaldehyde 62. After aqueous work-up, the solution was concentrated and diluted with acetonitrile to exchange solvents. Addition of commercially available 2,4-diamino-6-hydroxypyrimidine (63), aqueous sodium acetate and heating to 45??C resulted in cyclic condensation and precipitation of pyrrolo[2,3- d]pyrimidine 64 from the reaction mixture in 67% yield based on 60. Saponification of 64 with aqueous sodium hydroxide followed by acidification afforded the carboxylic acid derivative 65, which was elaborated to 66 by chlorodimethoxytriazine active ester coupling method. Reaction of 65 with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in the presence of N-methylmorpholine in DMF solution followed by reaction of the resulting dimethoxy-s-triazinyl ester with diethyl L-glutamate afforded crude 66, which was isolated via crystallization as pTSA salt 67. Saponification of 67 with aqueous sodium hydroxide followed by acidification with HCl gave pemetrexed as the free acid, which was crystallized as disodium salt form.

Drug interactions

Potentially hazardous interactions with other drugs
Antimalarials: antifolate effect increased by pyrimethamine.
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Nephrotoxic agents: may reduce clearance of pemetrexed - use with caution.
Live vaccines: avoid use; YELLOW FEVER VACCINE ABSOLUTELY CONTRAINDICATED.

Metabolism

Pemetrexed undergoes minimal hepatic metabolism, and about 70-90% of a dose is eliminated unchanged in the urine within 24 hours. In vitro studies indicate that pemetrexed is actively secreted by OAT3 (organic anion transporter).