Drug Review Pemetrexed for Injection Alimta Reviewer: Jamilah Al-Saedan B.Sc Pharm, King Saud University Introduction Malignant pleural mesothelioma A rare form of cancer. It is a malignant tumor of the mesothelial cells(these cells form the tissue called mesothelium), and arise primarily from the surface serosal cells of the pleural, peritoneal, and pericardial cavities. Once diagnosed fewer than 15% of patients survive past five years. Treatment with radiation has been disappointing, in part because of the difficulties in irradiating malignant tissue while avoiding toxicity to normal lung, cardiac, and spinal tissue. This cancer is associated with patients exposure to asbestos it is the main risk factor linked to mesothelioma asbestos is a mixture of silicates, iron, magnesium, nickel, cadmium, and aluminum, and has the unique property of occurring naturally as a fiber. It was widely used as fire retardant insulation of buildings. It's use has been banned in the U.S.A since approximately 1975, U.K in early 1980's. However, it is alarming that asbestos use in Saudi Arabia has not been documented. We may be dealing malignant mesothelioma in our hospitals or other asbestos related diseases but not relating it to the cancerous cause. Experts believe even minimal exposure could be fatal. Use of Alimta in conjunction with Cisplatin has been halted as the first significant breakthrough against mesothelioma. However it must be stated that its very unlikely it would induce curing of their disease. What it will do is prolong their life and reduce the chest pain and shortness of breath. Pemetrexed is considered an Orphan drug. Orphan drugs are developed to treat rare diseases, that is, conditions that affect fewer than 200,000 people in the U.S. The Orphan Drug Act provides a seven-year period of exclusive marketing for the drug to the first sponsor who obtains marketing approval for a designated orphan drug. Physical Description: Alimta is supplied as a sterile lyophilized powder for intravenous infusion available in single dose vials. The product is a white to either yellow or green-yellow lyophilized solid. Each 500mg vial of Alimta contains 500mg Pemetrexed and 500mg mannitol. Chemical Properties: Pemetrexed disodium heptahydrate has the chemical name: N-[4-{2-(2-amino-4,7- dihydro-4-oxo-1h-pyrrolol[2,3-d}pyrimidinyl)ethyl}benzoyl]- L- Glutamic acid, disodium salt, heptahydrate. The chemical structure is as follows: The chemical structure of folic acid is as follows:
Clinical Pharmacology: Pharmacodynamics: It exerts its antineoplastic activity by disrupting metabolic processes essential for cell replication-- as an anti-folate antimetabolite with multiple enzyme targets involved in both pyrimidine and purine synthesis. Mechanism of action: It inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. These are all folate dependent enzymes involved in the de-novo biosynthesis of thymidine and purine nucleotides. It has a pyrrole ring that replaces the pyrazine ring in the pterine portion of folic acid and a methylene group that replaces the benzylic nitrogen in the bridge portion of folic acid. Pemetrexed gains entry into the cell by reduced folate carrier and by membrane folate binding protein Transport systems. Once inside the cell, Pemetrexed is converted to polyglutamate forms by the enzyme folyl polyglutamate synthase, for which it shows high affinity. The polyglutamate forms are retained in cells and are inhibitors of thymidylate synthase (TS) and glycinamide ribonucleotide formyl transferase (GARFT), but not dihydrofolate reductase (DHF). The fact that it potently inhibits (TS), a highly expressed drug resistance related enzyme, may explain why Pemetrexed has activity in tumors refractory to standard treatment. Glutamation increases cellular retention of the drug molecule, which translates into both longer exposure time and increased intracellular concentrations of the drug. This thereby allows intermittent dosing of the drug. Evidence that Pemetrexed inhibits multiple enzyme targets is demonstrated by failure of coadministered thymidine to completely reverse Pemetrexed induced-toxicity in tumor cell lines. However administration of thymidine and a purine source such as hypoxanthine results in almost 100%reversal of cytotoxicity. Fig: 3- Some enzymatic reactions that use folates. Alimta acts at sections two and three. Pharmacokinetics: The drug is administered intravenously so absorption from the gastrointestinal tract isn t a concern. Pemetrexed plasma concentrations followed a two compartment model. (V ss) : The apparent steady state volume of distribution (Vss ) 6.8 L/m², which suggested that Pemetrexed is confined primarily to the plasma and interstitial compartments. This is consistent with the relatively highly polar nature of the compound. When given at the recommended dose of 600mg/m² the mean serum peak concentration reached is 137µg/ml and the half life ranges from 2.2-7.2 hr, the mean half life 3.1hr. Pemetrexed is not metabolized to an appreciable extent. It does not inhibit the cytochrome P-450 (CYP) iso-enzymes CYP3A4, CYP2D6, CYP1A2, CYP2C9. The clearance is primarily renal, with 78% of the dose recovered unchanged in the urine twenty-four hours after administration. The total systemic clearance is relatively high; 40mL per minute / m². No accumulation appears to occur after multiple courses and the linear disposition of Pemetrexed over the range studied does not change after
multiple treatment cycles. The C max and(auc) Area Under the Curve increase proportionally with the dose. As for protein binding, it is approximately 81% bound to plasma proteins. There have been no pharmacokinetic evaluations in patients with third space accumulations. Special Populations: The pharmacokinetics of Pemetrexed in special populations were examined in about 400 patients in controlled and single arm studies. Renal Failure: Pemetrexed is primarily eliminated unchanged by renal excretion. Plasma clearance of Pemetrexed in the presence of Cisplatin decreases as renal function decreases, whilst the (AUC) increases. No dosage adjustment is needed in patients with creatinine clearance 45mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45mL/min to give a dose recommendation. One patient had severe renal impairment with creatinine clearance of 19mL/min and died of drug related toxicity. The patient was not receiving Pemetrexed in combination with any other chemotherapeutic agent nor folic acid or Vitamin B12. Hepatic Insufficiency: Patients with bilirubin > than 1.5 times the upper limit of normal were excluded from clinical trials of Pemetrexed. Patients with transaminases greater than three times the upper limit of normal were routinely excluded from clinical trials unless they had hepatic metastases. There was no effect of elevated Aspartate aminotransferase, alanine aminotransferase or total bilirubin on the pharmacokinetic properties of Pemetrexed. Race: The pharmacokinetic properties were found to be similar in Caucasians and patients of African descent. Gender: The pharmacokinetic properties did not differ in male and female patients. Pediatric: Pediatric patients were not included in these trials, they began accepting candidates over 18 years of age. Dosage: Combination Use with Cisplatin: The recommended dose of Alimta and of Cisplatin Platinol ; Bristol Myers Squibb; Princeton, NJ) when used in combination: Alimta- 500mg/m² administered as an intravenous solution over ten minutes on Day one of each 21-day cycle. Cisplatin- 75mg/m² infused over two hours beginning approximately 30 minutes after the end of Alimta administration. Administration: Pemetrexed is available only as powder for reconstitution and should be administered as intravenous infusion. Each 500mg vial should be reconstituted with 20mL 0.9% Sodium Chloride Injection (preservative free) to give a solution containing 25mg/mL Alimta. The vials contents should be shaken gently to ensure powder is completely dissolved. The appropriate volume of reconstituted Alimta solution should be further diluted to 100mL with 0.9% Sodium Chloride Injection (preservative free). It should be administered as an intravenous infusion over ten minutes. Alimta is physically incompatible with diluents containing calcium, including Lactated Ringers Injection and therefore these should not be used. Pre-medication Regimen: Vitamin Supplementation: To reduce toxicity patients must be instructed to take both folic acid and vitamin B12.
Oral folic acid ( 350-1000µg )daily must be started 1 to 3 weeks before the first dose of chemotherapy and continued during the full course of therapy. The patient may take folic acid either as a low dose folic acid preparation or a multivitamin with folic acid. Experimentation in mice that nutritional folic acid supplements preserved the anti-tumor activity of Pemetrexed while drastically reducing toxicity. Patients must also receive one intramuscular injection of vitamin B12 (dose being 1000µg) during the week preceding the first dose of Alimta and every three cycles ( nine weeks) thereafter. Despite supplementation, the combination of Pemetrexed and Cisplatin produces a high degree of toxicity. Corticosteroid : Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone reduces the incidence of severity of cutaneous reaction. The recommended dose is 4mg orally twice daily on- the day before administration of Alimta, the same day, and the day after. Adverse Effects: Of course, a large range of side effects are to be expected because in an effort to kill the cancerous cells there is no doubt that healthy cells will be affected as well., and it is the damage to the healthy cells that may ultimately cause side effects. The cells most likely to be affected are the fast-growing normal cells such as the blood cells forming in bone marrow, and cells in the digestive tract which includes the mouth, stomach, intestines, and esophagus. Following therapy with Pemetrexed, toxicities appear to be higher in patients with elevated pre-therapy homocysteine levels. Elevated baseline homocysteine levels ( 10µmol/L) highly correlated with severe hematological and nonhematological toxicities. N5 methyl tetra hydro folate is required for the conversion of homocysteine to methionine. Impaired synthesis of N5 methyl tetra hydro folate results in elevated serum concentrations of homocysteine. There is a positive correlation between elevated serum homocysteine and occlusive vascular diseases such as ischemic heart disease and stroke. This data supports folic acid supplementation and proves its importance. Pemetrexed causes myelo-suppresion. The adverse effects common with Alimta use are primarily hematological and gastrointestinal side effects. The hematological disturbances includeneutropenia, leucopenia, anemia, and thrombocytopenia. The gastrointestinal effects include but are not limited to: Dysphagia, esophagitis, odynophagia, stomatitis, pharyngitis, constipation, nausea, vomiting, dehydration. Infections occur most likely due to neutropenia. The infection is rarely febrile. As for neurological disturbances, neuropathy, mood alterations ranging to depression also occur. There have been reports of rashes and skin desquamation, administration of dexamethasone helps ameliorate this. Unfortunately for malignant mesothelioma sufferers Alimta causes chest pain as well as dyspnea. Drug Interactions: As Alimta is to be administered with Cisplatin against malignant pleural mesothelioma, it is important that they do not interact negatively with eachother, otherwise they would not be recommended for this indication. The clearance of Pemetrexed is decreased by about 20% when administered concomitantly with
ibuprofen ( dose of ibuprofen 400mg four times daily.) Aspirin in low to moderate doses (325mg every six hours) does not affect the pharmacokinetics of Pemetrexed. However the affect of higher aspirin doses is not known. Alimta does not cause clinically significant interactions with drugs metabolized by cytochrome CYP3A, CYP2D6, CYP2C9, and CYP1A2. Pregnancy Category: Alimta may cause fetal harm when administered to a pregnant woman. It was classified as category D based on results of Pemetrexed trials in mice, there are no studies in pregnant women. Pemetrexed was feto-toxic and teratogenic in mice. It led to increased fetal deaths and decreased litter sizes. If Alimta is used during pregnancy, or if the patient becomes pregnant while using Alimta she should be apprised of the potential hazard to the fetus. Approved Indication: Alimta in combination with Cisplatin is indicated for the treatment of patients with malignant pleural mesothelioma whose disease is either unresectable or who are otherwise not candidates for surgery. This is the only indication for which it has been able to receive FDA approval. It received approval this year, the FDA announced it on the fourth of February 2004. Approval was based on survival as the superior clinical benefit. In a single, randomized, single blind, multi-center phase three trial, the efficacy and safety of Pemetrexed combined with Cisplatin were compared with those of single agent Cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive Cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the Pemetrexed plus Cisplatin treated arm and 9.3 months for the group treated with Cisplatin alone. Due to Pemetrexed's multi enzyme targets researchers have high hopes and preformed trials, which have led to the conclusion that :It shows anti tumor activity in breast, colorectal, bladder, head and neck, pancreatic, and gastric cancers. Pemetrexed has also undergone a trial for metastatic renal cancer, a malignant disease that is rising in incidence but remains difficult to treat. Alimta has yet to prove its place in therapy with further clinical trials, and receive FDA approval. Comparative Efficacy: There is no single or combination chemotherapy regimen that has shown to provide survival benefit for malignant pleural mesothelioma. Curative radiotherapy that exists is limited by tumor volume to be treated and by toxicities to surrounding normal tissue. Chemotherapy with single agents such as Doxorubicin, Methotrexate, 5-Fluorouracil and Gemcitabine appear to have limited activity. Gemcitabine and Cisplatin have been used in combination experimentally. In fact Pemetrexed is the first drug to be approved by the FDA for the sole purpose of treatment malignant pleural mesothelioma in combination with another drug. References: 1) Martin M., Spielman M, Namer M. et al. Phase II of Pemetrexed in breast cancer patients pretreated with Anthracyclines. Annals Oncology 2003;14:1246-1252. 2) Smit E. F, Mattson K, Von Pawel J. et. al. Alimta ( Pemetrexed Disodium as second line treatment of non-small-cell lung cancer: a phase two study. Annals of Oncology. 2003; 14: 455-460. 3) Clarke S. J, Abratt R, Goedhals L et. al. Phase two trial of Pemetrexed disodium ( ALIMTA, LY 231514) in chemotherapy naïve patients with advanced non-small-cell lung cancer. Annals of Oncology. 2003; 13:737-741.
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