What Are the Uses of Pemetrexed and Cisplatin?

Pemetrexed is an antifolate preparation that contains a pyrrolimidin group at its core. It destroys the normal folate-dependent metabolic processes in cells, inhibits cell replication, and thus suppresses tumor growth. In vitro studies have shown that pemetrexed can inhibit the activity of thymidylate synthase, dihydrofolate reductase, and glycine nucleotide formyltransferase, which are all enzymes necessary for the synthesis of folic acid and participate in the thymidine nucleus. In the process of biosynthesis of nucleotides and purine nucleotides, pemetrexed enters cells through a carrier carrying folic acid and a folic acid binding protein transport system on the cell membrane. Once pemetrexed enters the cell, it is converted into a polyglutamic acid form by the action of folyl polyglutamic acid synthase. Polyglutamic acid stays in the cell and becomes an inhibitor of thymidine synthase and glycine nucleotide formyltransferase. Polyglutamate presents a time-concentration-dependent process in tumor cells, but in normal tissues The concentration is very low. The half-life of polyglutamated metabolites in tumor cells is prolonged, which in turn extends the duration of drug action in tumor cells. Preclinical studies have shown that pemetrexed can inhibit the growth of mesothelioma cell lines (MSTO-211H, NCI-H2052) in vitro. Studies of the mesothelioma cell line MSTO-211H have shown synergy between pemetrexed and cisplatin.

Drug Name: Pemetrexed disodium for injection
Alias: ALIMTA
Foreign name: ALIMTA
Whether prescription drugs: prescription

Main indications: For the treatment of inoperable malignant pleural mesothelioma
Dosage: Please use under the guidance of a physician
Main medication contraindications: Special care should be taken when handling and configuring this product. Gloves are recommended
Athletes use with caution: Inadvertent use
Whether to include health insurance: Incorporate

Pemetrexed drug name

Common name: Pemetrexed disodium for injection

Product Name: English: ALIMTA

Chinese: Libitate

English name: Pemetrexeddisodium for Injection

Phonetic script: Zhu She YongPei Mei Qu Sai Er Na

The main ingredient of this product is pemetrexed disodium

Its chemical name and structural formula: slightly

Molecular formula: C20H19N5Na2O6 · 7H2O

Molecular weight: 597.49

Pemetrexed

This product is white to light yellow or green yellow freeze-dried solid.

Pemetrexed Pharmacology and Toxicology

Pemetrexed pharmacological effects

The index used for pharmacodynamic analysis of the population is absolute neutrophil count; at this time, the population received pemetrexed as a single drug and did not receive supplemental treatment of folic acid and vitamin B12. Judging the severity of hematological toxicity by observing the lowest value of granulocytes, it was found that it had a negative correlation with the systemic dose of this product. The study also found that if the patient had a high cystathionine or homocysteine concentration at baseline, the absolute granulocyte count would be even worse. Folic acid and vitamin B12; can reduce the concentration of two substrates, cystathionine or homocysteine. After pemetrexed multi-cycle treatment, no cumulative toxicity to neutrophils was seen.

After pemetrexed systemic administration (AUC 38.3-316. 8 g · hr / mL), the time taken for neutrophils to reach the lowest point was about 8-9. 6 days. After the lowest point, neutrophils The time taken for the count to return to baseline was 4.2-7.5 days.

Pemetrexed Toxicology Study

Genotoxicity: Micronucleus assays in mice bone marrow showed that pemetrexed was a rupture agent, but several experimental studies in vitro (Ames assay, CHO cell assay). None showed mutagenic effects. Reproductive toxicity: Pemetrexed is administered to male mice at a dose of 0.1 mg / kg / day or greater (equivalent to 1/1666 of the recommended dosage for humans), which can lead to reduced fertility, too little semen, and testicular atrophy.

Carcinogenicity: No studies have been conducted on the carcinogenicity of pemetrexed.

Pemetrexed kinetics

The pharmacokinetic evaluation of pemetrexed was performed in 426 patients with multiple tumor types. The drug was treated with a single drug at a dose of 0.2-838 mg / m2 and administered intravenously for 10 minutes. Pemetrexed is mainly excreted from the urinary tract in the form of the original drug. Within 24 hours after administration, 70% -90% of pemetrexed is reduced to the original form and excreted from the urine. The overall clearance rate of pemetrexed is 91.8 mL / min (the creatinine elimination rate is 90 mL / min). For patients with normal renal function, the body half-life is 3.5 hours; as renal function decreases, the clearance rate decreases, but The dose in the body will increase. As the pemetrexed dose increases, the area under the curve, AUC, and maximum plasma concentration (Cmax) increase proportionally. Multi-cycle treatment did not change the pharmacokinetic parameters of pemetrexed, and pemetrexed showed a steady state distribution volume of 16.1 liters. In vitro studies have shown that pemetrexed has a plasma protein binding rate of approximately 81% and is not affected by renal function.

Special population

The pharmacokinetic study in a special population of pemetrexed was a single-group study in a total of 400 patients. Elderly oneFor people aged 26-80 years, there is no significant change in the pharmacokinetics of pemetrexed.

ChildrenChildren were not included in the clinical study.

Gender-There is no difference in the pharmacokinetics of pemetrexed between male and female patients.

Race-Caucasian and African-American patients have similar pharmacokinetics to pemetrexed. There have been trials to study the pharmacokinetics of Japanese patients. Although there is no statistical comparison report of pharmacokinetic parameter specifications between Japanese patients and Western patients, it can still indicate that the absolute dose parameter values of the two are basically similar And there were no significant clinical differences.

Liver insufficiencyAspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) and total bilirubin are elevated, which do not affect the pharmacokinetics of pemetrexed. However, no pharmacokinetic studies have been performed in patients with liver damage. (See the "Patients with liver insufficiency" section under [Precautions]).

Renal insufficiencyA total of 127 patients with renal insufficiency have undergone pemetrexed pharmacokinetic studies. If combined with cisplatin, the plasma clearance of pemetrexed decreases as renal function decreases, and the systemic exposure dose increases. Comparing the total systemic exposure (AUC) of pemetrexed with the creatinine clearance of 100 mL / min, the total systemic exposure (AUC) increased by 65% and 54% when the creatinine clearance was 45, 50, and 80 mL / min, respectively. And 13%. (See the "Warning" section under [Usage] and [Precautions])

Pemetrexed indications

This product is used in combination with cisplatin to treat malignant pleural mesothelioma that cannot be operated on.

Pemetrexed usage and dosage

This product should be used under the guidance of a qualified physician with experience in the application of antitumor chemotherapy. This product can only be used for intravenous drip, and its solution must be prepared according to the instructions for "intravenous drip preparation".

Pemetrexed pleural mesothelioma

The recommended dose of this product in combination with cisplatin for the treatment of malignant pleural mesothelioma is 500 mg / m2 infusion over 21 minutes every 21 days, and the recommended dose of cisplatin is 75 mg / m2 infusion over 2 hours. Thirty minutes after the end of the administration, a cisplatin drip was given. Treatment with cisplatin requires a hydration regimen. For details, refer to the cisplatin manual.

Pemetrexed

Corticosteroids-Patients who do not pre-administer corticosteroids have a higher incidence of rashes with this product.

Pretreatment with dexamethasone (or similar drugs) can reduce the incidence and severity of skin reactions. Administration method: Dexamethasone 4mg orally twice daily,

Take this product one day before administration, one day after administration, and one day after administration for three consecutive days.

Vitamin supplement 1 In order to reduce toxic reactions, this product must be treated with low-dose folic acid or other multivitamin preparations containing folic acid.

Pemetrexed time

Folic acid should be taken at least 5 daily doses 7 days before the start of the first treatment of this product, which has been taken throughout the treatment cycle, and can be discontinued 21 days after the last dose of this product. Patients also need to inject vitamin B12 intramuscularly within 7 days before the first administration of this product, and then intramuscularly every 3 cycles thereafter. The subsequent administration of vitamin B12 can be performed on the same day as the administration of this product. Folic acid administration dose: 350-1000g, commonly used dose is 400g: Vitamin B12 dose is 1000g. (See the "Warning" section under [Caution]).

Pemetrexed dosage usage

MonitoringAll patients who are preparing to receive this product should complete a blood cell examination including platelet count before administration, and monitor blood cells after administration

The lowest point and recovery, the above items should be checked at the beginning of each cycle, on the 8th and 15th days of the clinical study. Patients can only start this product when the neutrophils are 1500 / mm3, the platelets are 100,000 cells / mm3, and the creatinine clearance is 45mL / min. Each cycle of treatment requires biochemical examination of liver function and kidney function. The recommended dose adjustment method is based on the lowest blood cell count and the most severe non-hematological toxicity in the previous cycle. If the patient does not recover from the adverse reactions in the 21-day cycle, treatment should be delayed.

If the patient has experienced 3/4 degree hematological or non-hematological toxicity (excluding 3 degree transaminase elevation) after 2 dose adjustments, this product should be discontinued. If 3 or 4 degree neurotoxicity occurs, immediately Stop treatment.

Elderly patients-Patients 65 years of age do not need special adjustments in addition to the above-mentioned dose adjustment scheme.

Children-This product is not recommended for children, and the safety and effectiveness of children's medication have not been determined.

Patients with renal insufficiencyAs long as the creatinine clearance of the patient is 45mL / min, the dose adjustment method is performed for all patients, and there is no special dose adjustment method. A dose adjustment method for creatinine clearance below 45 mL / min has not been determined. Therefore, when the creatinine clearance calculated by the Cockcroft-Gault formula or the glomerular filtration rate calculated by the Tc99m-DPTA serum clearance method is <45mL / min, this product should not be given treatment.

[140Age] × Actual weight (kg)

Male: = mL / min

72 × serum creatinine (mg / dL)

Female: Male creatinine clearance × 0.85

In patients with creatinine clearance <80mL / min, if this product is combined with non-steroidal anti-inflammatory drugs should be vigilant and monitored closely. (See [Drug Interactions])

People with liver dysfunction-This product is not metabolized by the liver. See Table 2 for dose adjustment for liver dysfunction. (Refer to the "Precautions" section under "Patients with liver insufficiency").

Pemetrexed notes

This product is an antitumor drug. Like other potentially toxic antineoplastic drugs, special care must be taken when handling and configuring this product. Gloves are recommended. If the injection of this product comes into contact with the skin, immediately wash thoroughly with soap and water. If the injection of this product comes into contact with mucous membranes, wash thoroughly with water. There are no uniform recommendations for the treatment of anticancer drugs.

This product is not an erosive agent and has no specific antidote. So far, there have been several reports of extravasation of this product injection, but the researchers believe that it is not serious. The extravasation treatment of this product can be carried out according to the conventional method of non-erosive treatment.

Pemetrexed drip preparation

1. The configuration process should be performed aseptically.

2. Calculate the dosage of this product and the number of medications. Each medicine contains 500mg of this product. Each bottle actually contains more than 500mg of this product to ensure that the labeled amount can be reached during intravenous drip.

3. Each 500mg drug is dissolved into a solution of this product with a concentration of 25mg / mL with 20mL of 0.9% sodium chloride injection (without preservatives), and slowly rotated until the powder is completely dissolved. After the solution is completely dissolved, the color is normal to colorless to yellow or yellow-green. The pH value of this solution is 6.6-7.8. And the solution needs to be further diluted.

4. Observe the solution for precipitation and color change before intravenous drip: if there is something abnormal, do not drip.

5. After the drop of the product is prepared, it should be diluted to 100 mL with 0.9% sodium chloride injection (without preservatives), and intravenously infused over 10 minutes.

6. The prepared solution is stored in the refrigerator or at room temperature (15-30 ° C). It does not need to be protected from light. Its physical and chemical properties remain stable for 24 hours. The solution of this product prepared according to the above method does not contain antibacterial preservatives. Do not discard partially. This product is only recommended to be dissolved and diluted with 0.9% sodium chloride injection (without preservatives). This product is insoluble in calcium-containing diluents, including USP Ringer's Lactate Injection and USP Ringer's Injection. Whether other diluents and other drugs can be mixed with this product has not been determined, so it is not recommended.