What Is Temozolomide Chemotherapy?

The drug substance of temozolomide is a white or light brown / light pink powder with a relative molecular mass of 194.15. Decomposes easily at pH 7, crystallizes from dichloromethane, melting point 212 ° C (decomposed). UV absorption (95% ethanol): 327 nm. It is slightly soluble in dimethyl sulfoxide, slightly soluble in water, very slightly soluble in methanol, almost insoluble in ethanol, and slightly soluble in glacial acetic acid. It is used clinically to degrade spontaneously and quickly in the body to produce the active metabolite MTIC, which has an antitumor effect.

Chinese name: Temozolomide
Foreign name: Temozolomide

CAS number: 85622-93-1
Molecular formula: C6H6N6O2

Introduction to temozolomide compounds

Temozolomide Basic Information

Chinese name: Temozolomide

Chinese alias: 3-methyl-4-oxo-8-imidazo [5,1-d] [1,2,3,5] tetrazinecarboxamide; 8-carbamoyl-3-methylimidazole [ 5,1-d] benzo-1,2,3,5-tetrazazine-4- (3H) -one; 4-methyl-5-oxo-2,3,4,6,8-pentaza Heterobicyclo [4.3.0] nonyl-2,7,9-triene-9-carboxamide; 3,4-dihydro-3-methyl-4-oxoimidazo [5,1-d]- 1,2,3,5-tetrazine-8-carboxamide; 8-carbamyl-3-methylimidazole [5,1-d] -1,2,3,5-tetrazine-4 (3H) -Keto; temetazol; 4-methyl-5-oxo-2,3,4,6,8-pentaazabicyclo [4.3.0] non-2,7,9-triene-9- Formamide

English name: Temozolomide

English alias: temodar; TZM; Temozolamide; temosolomide;

CAS number: 85622-93-1

MDL number: MFCD00866492

RTECS number: NJ5927050

Molecular formula: C ₆ H ₆ N ₆ O ₂

Structural formula:

Molecular weight: 194.15100

Exact mass: 194.05500

PSA: 108.17000 ^[1]

Temozolomide physical and chemical properties

Appearance and properties: off-white to light pink crystalline solid

Density: 1.97 g / cm ³

Melting point: 212 ° C dec.

Boiling point: 526.6ºC at 760 mmHg

Flash point: 272.3ºC

Storage conditions: 2-8ºC

Temozolomide Safety Information

Symbol: GHS07; GHS08

Signal Word: Danger

Hazard statement: H302; H315; H319; H335; H350; H360

Cautionary statements: P201; P261; P305 + P351 + P338; P308 + P313

Customs code: 2933990090

Danger category code: R45

Safety instructions: S24 / 25; S45; S36 / 37; S26; S53

RTECS number: NJ5927050 ^[1]

Dangerous Goods Mark: T; Xi

Calculating Chemical Data for Temozolomide

1. Hydrophobic parameter calculation reference value (XlogP): None

2.Number of hydrogen-bonded donors: 1

3.Number of hydrogen bond acceptors: 5

4.Number of rotatable chemical bonds: 1

5.Number of tautomers: 2

6. Topological molecular polar surface area 106

7.Number of heavy atoms: 14

8.Surface charge: 0

9.Complexity: 315

10.Number of isotope atoms: 0

11. Determine the number of atomic stereocenters: 0

12. Uncertain number of atomic stereocenters: 0

13. Determine the number of chemical bond stereocenters: 0

14. Uncertain number of chemical bond stereocenters: 0

15. Number of covalent bond units: 1 ^[2]

Temozolomide synthesis method

1. After diazotization of 5-amino-4-carboxamidoimidazole with nitrous acid, it is reacted with methyl isocyanate in dichloromethane to cyclize to obtain temozolomide.

2. Preparation of 5-aminoimidazole-4-carboxamide hydrochloride

Add 47.4g (0.2mol) of industrial 2-fluorenyl-2-carboxamidoacetamide hydrochloride and 150ml of xylene to the reaction flask. Stir and heat to reflux in the oil bath (approximately 130 ~ 140 ºC, then slowly Reduce to 118 ~ 120 ºC, keep it at reflux for 3h. Filter out the xylene while hot, wash the crystals with 60ml of fresh xylene, and concentrate to dryness under reduced pressure, add 100ml of absolute ethanol, wash, cool, crystallize, filter, filter cake After drying under reduced pressure below 50 ºC, 27.9 g of 5-aminoimidazole-4-carboxamide hydrochloride was obtained with a yield of 85.8%.

3. Preparation of 5-amino-imidazole-4-carboxamide (monohydrate)

Add 27.9 g (0.170 mol) of 5-aminoimidazole-4-carboxamide hydrochloride and 50 ml of deionized water to the reaction flask, stir to dissolve slightly, add NaOH (10% aqueous solution) dropwise at 30 ºC to about pH 7, Add insurance powder, appropriate amount of (Na2S2O4), freeze and place overnight, filter, wash the filter cake with a small amount of ice water, and vacuum dry at 60 ºC to obtain 23.6g of 5-amino-imidazole-4-carboxamide (monohydrate), yield 95% , mp174 ~ 176 ºC.

4. Preparation of 5-diazoimidazole-4-carboxamide

In a constant pressure dropping funnel, add a mixed solution of 26 g (0.180 mol) of 5-amino-imidazole-4-carboxamide (monohydrate) and 300 ml of 1 mol / L hydrochloric acid, and slowly add it to NaNO220 with stirring at 0 ~ 5ºC. .7g (0.3mol) in a 100ml reaction flask with water, dripping is completed in about 30min. After dripping, keep stirring for 30min, TLC tracks the reaction [developing solvent: methanol / ethyl acetate (volume ratio 2: 3)]. To the end of the reaction After that, it was concentrated under reduced pressure until a small amount of crystals appeared, cooled, crystallized, filtered with suction, washed with a small amount of water, and dried under reduced pressure at 40 ºC to obtain yellow diazonium crystals. -4-Carboxamide 22.4g, yield 71% .mp205 ~ 208ºC.

5. Synthesis of Temozolomide

Add 22 g (0.125 mol) of 5-diazoimidazole-4-carboxamide, 43 ml (41.27 g, 0.724 mol) of methyl isocyanate and 100 ml of ethyl acetate / DMF (volume ratio 3: 1) to the reaction flask. The reaction was stirred at room temperature (25 ~ 30 ºC) in the dark for 40 hours, filtered, and the filter cake was washed with ethyl acetate. The crude temozolomide was dried under reduced pressure and reduced pressure to obtain 24.1 g of the crude temozolomide, with a yield of 99%. 3: 2) Dissolve and mix in 100ml, then add a little activated carbon, heat under reflux for 20 ~ 25min, heat filter, and cool the crystals to crystallize to obtain 19.4g of refined temozolomide, yield 80%, mp210 ~ 213 ºC. ^[2]

Temozolomide uses

Antitumor drugs. It can spontaneously and quickly degrade in the body to produce the active metabolite MTIC, which has an antitumor effect. Used as a treatment for adult malignant glioma and malignant melanoma.
This product is an anti-tumor drug. It can spontaneously and quickly degrade in the body to produce the active metabolite MTIC, which produces an anti-tumor effect. This product is an azene imidazole in an alkylating agent anti-tumor drug, similar to mitozod It is one of the most effective drugs for clinical treatment of brain tumors. Studies have shown that it has obvious effects on various experimental tumors in animals, including TLX5 lymphoma. Oral administration of this product to the brain of athymic mice by subcutaneous transplantation The tumor has obvious curative effect. It can pass the blood-brain barrier, clinically treat brain or intrathecal tumors and advanced melanoma brain metastases, as well as adult refractory pleomorphic glioblastoma, etc. It has small toxic side effects and good tolerance. ^[2]

Temozolomide Pharmacopoeia Standard

Temozolomide molecular formula and molecular weight

C6H6N6O2 194.15

Temozolomide source (name), content (potency)

This product is 3,4-dihydro-3-methyl-4oxoimidazole [5,1-d] and 1,2,3,5-tetrazine-8-carboxamide. Calculated on dry basis, containing C6H6N6O2 should be 98.0% to 102.0%.

Temozolomide traits

This product is white to reddish powder; odorless.

This product is slightly soluble in dimethyl sulfoxide, slightly soluble in water, very slightly soluble in methanol, almost insoluble in ethanol, and slightly soluble in glacial acetic acid.

Temozolomide identification

(1) Take this product, add glacial acetic acid solution (5 1000) to quantitatively dilute it to make a solution containing about 10g per 1ml, and measure it by UV-visible spectrophotometry (Appendix IVA of Pharmacopoeia Part II of the 2010 edition). There is a maximum absorption at a wavelength of 330 nm, and a minimum absorption at a wavelength of 240 nm and 279 nm.

(2) In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution.

(3) The infrared absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Medicine" 1216).

Temozolomide test

relative substance

Take this product, add mobile phase to dissolve and dilute it to make a solution containing 1.0mg per 1ml, as a test solution; take an appropriate amount of 4-amino-5-carbamoylimidazole monohydrate reference, and dissolve in mobile phase. And dilute to make a solution containing 1.0 mg per 1 ml as the reference solution; precisely measure 1 ml each of the test solution and the reference solution, place them in the same 200 ml volumetric flask, dilute to the mark with the mobile phase, and shake as Control solution. According to the chromatographic conditions under the content determination item, 20 l of the control solution was injected into the liquid chromatograph, and the order of the peaks was: 4-amino-5-carbamoylimidazole and temozolomide. Adjust the detection sensitivity so that the peak height of the temozolomide chromatographic peak is approximately 10% of full scale. Then, 20 l of each of the test solution and the control solution was precisely measured and injected into the liquid chromatograph respectively, and the chromatogram was recorded to 2.5 times the retention time of temozolomide peak. If there is a 4-amino-5-carbamoylimidazole peak in the chromatogram of the test solution, the peak area should not be larger than the temozolomide peak area of the control solution (0.5%) 0.5%); the sum of the peak areas of each impurity should not be greater than two times (1.0%) the peak area of temozolomide in the control solution.

Dimethyl sulfoxide

Weigh accurately 25mg of dimethyl sulfoxide, place it in a 100ml measuring bottle, dilute to the mark with N, N-dimethylformamide, shake well, take 5ml precisely, place it in a 10ml measuring bottle, and add the internal standard solution ( Take an appropriate amount of N-methylpyrrolidone, add N, N-dimethylformamide to make a solution containing about 1mg per 1ml) 1ml, dilute to the mark with N, N-dimethylformamide, shake well, as a control 0.25g of this product, accurately weighed, placed in a 10ml measuring bottle, accurately added 1ml of internal standard solution, diluted to the mark with N, N-dimethylformamide, shake well, as the test solution. Tested according to the residual solvent determination method (Appendix P, Part III, Pharmacopoeia, Part Two, 2010 edition). Polyethylene glycol was used as the fixing solution; the column temperature was 200 ° C, and the detector temperature was 240 ° C. Precisely measure 1 l each of the test solution and the reference solution, and inject them into the gas chromatograph respectively to record the chromatogram. Calculated by peak area according to the internal standard method, it should meet the requirements.

Loss on drying

Take 1.0g of this product, put it in a phosphorus pentoxide dryer, and dry it under reduced pressure at 60 ° C to constant weight, and the weight loss shall not exceed 0.5% (Appendix L of Part Two of the Pharmacopoeia, 2010 Edition).

Residue on ignition

Take 1.0Og of this product and check it according to law (Appendix N of Part Two of the Pharmacopoeia of 2010 Edition). The residual residue shall not exceed 0.1%.

Heavy metal

Take the remaining residue under the burning residue and check it according to law (Appendix H, the second method of the 2010 edition of the Pharmacopoeia, the second method). The content of heavy metals must not exceed 10 parts per million.

Determination of temozolomide

It was determined by high performance liquid chromatography (Appendix VD of Part Two of the Pharmacopoeia, 2010 Edition).

Chromatographic conditions and system suitability tests

Octadecylsilane-bonded silica gel was used as the filler; methanol-0.5% glacial acetic acid solution (10:90) was used as the mobile phase} The detection wavelength was 254 nm. The number of theoretical plates calculated from the temozolomide peak is not less than 9000, and the resolution of the temozolomide peak from the adjacent impurity peaks should meet the requirements.

Assay

Take an appropriate amount of this product, accurately weigh it, add the mobile phase to dissolve and quantitatively dilute it to a solution containing about 0.1 mg of temozolomide per 1ml, accurately measure 20 l into the liquid chromatograph, and record the chromatogram; take another temozolomide reference substance, the same method Determination. Calculate the peak area according to the external standard method. ^[3]

Temozolomide pharmacological effects:

Temozolomide is an alkylating agent with antitumor activity of imidazo tetrazines. At the physiological pH state of the systemic circulation, it is rapidly converted into the active product MTIC (3-methyl- (triazine-1-) imidazole-4-carboxamide). The cytotoxic effect of MTIC is mainly manifested by the alkylation of the guanine oxygen atom at the 6th position and the alkylation of the nitrogen atom at the 7th position. Through the mismatch repair of methylated adducts, it exerts cytotoxicity. ^[4]

Temozolomide Toxicology Study:

A single dose toxicity study of this product was performed in mice, rats and dogs. The oral LD50 of rats is about 1900 mg / m, which is higher than that of mice (about 1000 mg / m). The minimum lethal dose to dogs is 600 mg / m. In single-dose studies, clinical signs and death of toxicity generally appear later, indicating that it has a late toxic effect on tissues that cause rapid proliferation of organ damage; the toxic effect is consistent with the expected toxicity of alkylating agents.

After oral administration, the product is quickly absorbed and excreted into the urine. Human exposure to therapeutic doses is similar to that of rats and dogs. Toxicity studies in rats and dogs have been performed in 3 and 6 cycles, with one cycle consisting of 5 days of dosing and 23 days of discontinuation. In multi-cycle studies, the main toxic target organs are the bone marrow, lymphatic reticulum, testis, and gastrointestinal tract. This product is more toxic to rats and dogs than to humans. Humans are well tolerated at the therapeutic dose (200 mg / m), but this dose is close to the lowest lethal dose of multiple doses in rats and dogs. Dose-related reductions in white blood cells and platelets are sensitive indicators for rats and dogs. During the treatment period, most hematological and biochemical indicators as well as histopathological changes can be significantly recovered. The tumor spectrum examined in the 6-cycle rat study includes breast cancer, keratoderma acanthoma, basal cell adenoma, and various stromal tumors. No tumors or precancerous changes were examined in the dog study. Considering that this product is a prodrug of the alkylating agent MTIC, it is expected to have a tumorigenic effect, which has been observed in other alkylating agents, including those that produce MTIC. The tumorigenic effect of this product on rats seems to be species-specific and has no significant difference from other chemotherapeutic drugs.

This product Ames / Salmonella and HPBL tests have shown mutagenic effects, and can cause chromosomal aberrations in the measurement of human peripheral lymphocytes. ^[4]

Temozolomide Pharmacokinetics:

Preclinical data suggest that this product can quickly cross the blood-brain barrier and enter the cerebrospinal fluid. Adult patients are quickly absorbed after oral administration of this product, and peak plasma concentrations can be reached as early as 20 minutes after taking the drug (average time is 0.5-1.5 hours). Plasma clearance, volume of distribution, and half-life are independent of dose. This product has a low protein binding rate (10% -20%), so it is estimated that it will not interact with drugs with high protein binding rate. The C excreted in the feces within 7 days after oral administration of this product was 0.8%, indicating that the drug was completely absorbed. After oral administration, the original drug in the urine for 24 hours accounts for about 5% -10% of the dose, and the rest is excreted into the urine in the form of AIC (4-amino-5-imidazole-carboxamide hydrochloride) or other polar metabolites.

Population analysis of pharmacokinetics of this product shows that plasma clearance of this product is not related to age, renal function, or smoking.

The AUC of pediatric patients is higher than that of adult patients, but the maximum tolerated dose (MTD) per cycle for children and adults is 1000 mg / m. ^[4]

Temozolomide indications:

This product is used to treat:

-Newly diagnosed glioblastoma multiforme is started with radiotherapy and then used as adjuvant therapy.

-Glioblastoma multiforme or anaplastic astrocytoma that relapses or progresses after conventional treatment. ^[4]

Temozolomide Usage and Dosage:

Adult patients with temozolomide newly diagnosed glioblastoma multiforme:

Concurrent chemoradiotherapy period: oral administration of this product at a daily dose of 75mg / m for a total of 42 days, and concurrently receiving radiotherapy (60 Gy points 30 times); subsequently receiving 6 cycles of adjuvant treatment with this product. Medication can be suspended based on the patient's tolerance, but the dose need not be reduced. If the following conditions are met during concurrent chemoradiotherapy: absolute white blood cell count 1.5 × 10 / L, platelet count 1.5 × 10 / L, common toxicity standard (CTC)-non-hematological toxicity grade 1 (except hair loss, nausea and vomiting) This product can be used continuously for 42 days up to 49 days. A full blood count should be performed weekly during treatment. Suspension or discontinuation of this product during concurrent chemotherapy should be based on hematological and non-hematological toxicity criteria (Table 1).

If you meet the following criteria, you can continue to treat with TMZ at the same time: absolute white blood cell count 1.5 * 10 / L, platelet count 1.5 * 10 / L, CTC-non-hematological toxicity Grade 1 (except hair loss, nausea and vomiting)
TMZ = this product; CTC = common toxicity standard

Adjuvant treatment period: 4 weeks after the end of the concurrent chemoradiotherapy period, 6 cycles of adjuvant treatment of this product. The dose of this product in the first cycle is 150 mg / m / day, once a day for 5 days, and then discontinued for 23 days. At the beginning of the second cycle, if the non-hematological toxicity of CTC of the first cycle is 2 (except for hair loss, nausea and vomiting), absolute white blood cell count (ANC) 1.5 × 10 / L and platelet count 100 × 10 / L, The dose can be increased to 200 mg / m / day. If the dose is not increased in the second cycle, it should not be increased in subsequent cycles. With the exception of toxicity, the subsequent doses were maintained at 200 mg / m daily. During adjuvant therapy, the dose should be reduced according to Tables 2 and 3.

During treatment, a complete blood count should be performed on day 22 (21 days after the first dose of this product). The dose should be reduced or discontinued according to Table 3.

a: See Table 2 for TMZ dose levels.
b: If it is necessary to reduce TMZ to <100mg / m, or if the same Grade 3 non-hematological toxicity (except hair loss, nausea and vomiting) reappears after reducing the dose, TMZ treatment should be discontinued.
TMZ = this product; CTC = common toxicity standard <br Patients with glioblastoma multiforme or anaplastic astrocytoma who have relapsed or progressed after conventional treatment:

Adult patients: The starting dose of this product is 150 mg / m / day for 5 days in patients who have previously received chemotherapy. If the first day of the next cycle is ANC1.5 × 10 / L and platelet count 100 × 10 / L, the dose in the second cycle increased to 200 mg / m / day. The dose of this product should be adjusted according to the minimum values of ANC and platelet count.

Pediatric patients: In children who have previously received chemotherapy 3 years old or older, the initial oral dose of this product is 150 mg / m / day for a total of 5 days in each 28-day cycle; if there is no toxicity, the next The periodic dose was increased to 200 mg / m / day.

Treatment can continue until the disease progresses, up to 2 years.

Laboratory parameters for dose adjustment

The following laboratory parameters must be met before administration: ANC 1.5 × 10 / L and platelet count 100 × 10 / L. On day 22 (21 days after the first dose) or within 48 hours of that day and every week, a complete blood cell count must be checked until ANC 1.5 × 10 / L and platelet count 100 × 10 / L. If ANC <1.0 × 10 / L or platelet count <50 × 10 / L in any one cycle, the dose in the next cycle must be reduced by one level. Dose levels include 100 mg / m, 150 mg / m, and 200 mg / m. The recommended minimum dose is 100 mg / m.

All patients: This product should be taken on an empty stomach (at least one hour before a meal). Antiemetics can be used before and after taking this product. If vomiting occurs after taking the medicine, do not take the second dose on the day.

Do not open or chew this product, swallow it whole with a glass of water. If the capsule is damaged, contact of the skin or mucous membranes with the powdery contents of the capsule should be avoided. ^[4]

Temozolomide contraindications:

Those who are allergic to temozolomide capsules or dacarbazine (DTIC) are contraindicated.
Banned during pregnancy (see Medications for pregnant and lactating women)
Disabled in patients with severe bone marrow suppression. ^[4]

Temozolomide Adverse Reactions

The main adverse reactions of this product include nausea, vomiting, burnout and hematological reactions. Nausea, vomiting, headache and burnout occur most frequently. These adverse reactions are usually NCI common toxicity criteria (CTC) grade 1 or 2 (mild to moderate), and are self-limiting. Nausea and vomiting can be controlled with antiemetics. The incidence of severe nausea and vomiting (CTC grade 3 or 4) was 10% and 6%, respectively. Myelosuppression is a dose-limiting adverse reaction that usually occurs during the first cycle of treatment and does not accumulate. ^[5]

Adult patients with temozolomide glioma recurrence or progression

In clinical trials, the most common adverse reactions were gastrointestinal dysfunction, especially nausea (43%) and vomiting (36%); generally grade 1 or 2 (mild to moderate), self-limiting, or standard Antiemetics are easy to control. The incidence of severe nausea and vomiting was 4%.

Other frequently reported adverse events include fatigue (22%), constipation (17%), and headache (14%). Anorexia (11%), diarrhea (8%), and rash, fever, weakness, and drowsiness were also reported as 6% each. Uncommon (2% -5%) adverse events in decreasing order of incidence are abdominal pain, pain, dizziness, weight loss, discomfort, dyspnea, hair loss, stiffness, itching, indigestion, abnormal taste, paresthesia and petechia .

Laboratory results: The incidence of grade 3 or 4 thrombocytopenia and neutropenia in glioma patients was 19% and 17%, respectively. 8% and 4% of glioma patients were hospitalized and / or discontinued. Myelosuppression is predictable (usually on days 21-28 of the first few cycles) and usually recovers quickly within 1-2 weeks. No cumulative bone marrow suppression was found. Pancytopenia, leukopenia, and anemia have also been reported; lymphopenia is also common.

Analysis of the pharmacokinetics population in clinical trials showed that the number of neutrophils reached 101, females and 169 men; platelets reached minimums, 110 women, and 174 men. The incidence of grade 4 adverse reactions in the first cycle of treatment was higher in women than men, among which neutropenia (ANC <500 cells / L) was 12% in women and 5% in men; thrombocytopenia (<20,000 cells / L) in women was 9% , 3% male. In a group of 400 patients with recurrent glioma, the incidence of grade 4 neutropenia in the first cycle of treatment was 8% and 4% for women and men, respectively; and grade 4 thrombocytopenia The incidence rates were 8% and 3%, respectively. In another newly diagnosed multiline glioblastoma trial with 288 subjects, the incidence of grade 4 neutropenia in the first cycle of treatment was 3% for women and 0 for men. %; The incidence of grade 4 thrombocytopenia was 1% and 0%, respectively.

During the marketing period of this product, few cases of opportunistic infections were reported, including pneumocystis carinii pneumonia. Rarely, erythema polymorpha, toxic epidermal necrosis, Sjogold's syndrome, and allergic (including allergic) cases have been reported. Rare cases of myelodysplastic syndrome (MDS) and secondary malignant diseases (including myeloid leukemia) have been reported in patients receiving this product. There have been reports of pancytopenia that have been reported to cause aplastic anemia, and fatal consequences have occurred in some cases. Cases of liver toxicity that have been reported include elevated liver enzymes, hyperbilirubinemia, cholestasis, and hepatitis.

No unexpected adverse events occurred in clinical studies conducted in China, and the overall results were similar to data reported abroad. ^[4]

Tips for temozolomide

In a small-scale trial with treatment duration extended to 42 days, patients receiving concomitant therapy with this product and radiotherapy were at high risk for pneumocystis carinii pneumonia. Therefore, prevention of Pneumocystis carinii pneumonia is needed for all patients who receive concomitant treatment for 42 days (up to 49 days).

During longer-term dosing regimens, the incidence of Pneumocystis carinii pneumonia may be higher during temozolomide treatment. Regardless of the treatment option, all patients treated with temozolomide (especially those receiving steroids) should be closely monitored for the possibility of developing pneumocystis carinii pneumonia.

Antiemetic treatment: Nausea and vomiting are often related to this product. Antiemetics can be used before and after taking this product. The guiding principles are:

Patients with temozolomide newly diagnosed with glioblastoma multiforme:

-Antiemetic prophylaxis is recommended before commencing temozolomide,

-During adjuvant therapy, antiemetic prophylaxis is highly recommended.

Patients with glioma recurrence or progression: Patients who have experienced severe (grade 3 or 4) vomiting in previous treatment cycles need antiemetic therapy.

Patients receiving temozolomide may experience bone marrow suppression, including sustained reductions in whole blood cells, which may lead to aplastic anemia, and in some cases have fatal results. In some cases, taking other medications related to aplastic anemia (including carbamazepine, phenytoin, and compound sulfamethoxazole) can make assessment more difficult.

Male patients : Male patients taking temozolomide should take effective contraception. Temozolomide is genotoxic, so men should have contraception during the course of treatment and within 6 months after the end of treatment. Because treatment with temozolomide may cause irreversible infertility, sperm should be stored frozen before receiving this treatment.

Patients with impaired liver and kidney function : Patients with normal liver function have similar pharmacokinetic results to patients with mild to moderate abnormal liver function; patients with severe liver dysfunction (Child's Class III) or renal dysfunction have no data on taking temozolomide. According to the pharmacokinetic characteristics of temozolomide capsules, it is not necessary to reduce the amount of temozolomide in patients with severe hepatic and renal insufficiency, but caution must be exercised when using it.

Temozolomide for pregnant and lactating women:

The use of the drug in pregnant women has not been studied. In preclinical studies in rats and rabbits, teratogenic and / or fetal toxicity have been reported at 150 mg / m. Therefore, temozolomide should not be routinely used in pregnant women. If the drug must be used during pregnancy, the patient should be informed of the potential risks to the fetus. Women who are likely to become pregnant should be discouraged from getting pregnant within 6 months of temozolomide treatment or termination of temozolomide treatment.

Whether temozolomide can be secreted by breast milk is unknown, so temozolomide capsules should not be used in lactating women.

Temozolomide for children:

There is no clinical experience of using the drug in children with glioblastoma multiforme under 3 years of age; the clinical experience of using the drug is limited for children over 3 years of age.

Temozolomide for the elderly:

Compared with young patients, elderly patients (> 70 years) are more likely to have neutropenia and thrombocytopenia. ^[4]

Temozolomide Drug Interactions:

There was no clinical significance of the effect of concurrent taking ranitidine or food on the absorption of temozolomide capsules. Taking dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists, or phenobarbital at the same time did not affect the clearance of temozolomide. When taking valproic acid at the same time, temozolomide clearance was slightly reduced (statistically significant).

When temozolomide capsules are used in combination with other drugs that cause bone marrow suppression, bone marrow suppression may worsen. ^[4]

Temozolomide overdose:

Clinical evaluations have been performed in patients at doses of 500, 750, 1000, and 1250 mg / m (total dose administered for 5 days per treatment cycle). Dose-limiting toxicity is hematological toxicity, which has been reported at any dose, but is more severe at higher doses. One patient overdosed 2000 mg daily for 5 days. The reported adverse events were pancytopenia, fever, multiple organ failure, and death. Adverse events in patients taking the drug for more than 5 days (up to 64 days) included myelosuppression (with or without infection), and some severe and persistent cases eventually died. In the event of an overdose, a hematological evaluation should be performed. Supportive measures should be taken when necessary. ^[4]

Temozolomide Expert Reviews

A multicenter study of 162 patients with first relapsed glioblastoma multiforme was performed in 54 patients with refractory glioblastoma multiforme (i.e. The condition worsened during the benzylhydrazine chemotherapy regimen). The overall tumor response rate (CR + PR) of this population was 22% and the complete response rate was 9%. All responses were maintained for an average of 50 weeks (16 to 114 weeks) and complete responses were maintained for an average of 64 weeks (52 to 114 weeks). In this population, the survival rate without deterioration at 6 months was 45% (95% confidence interval is 31% to 58%); the survival rate at 12 months was 29% (95% confidence interval 16% ~ 42%); the average survival time without deterioration was 4.4 months. The overall survival rate at 74 months is 74% (95% confidence interval is 62% to 86%); the overall survival rate at 12 months is 65% (95% confidence interval is 52% to 78%); the average overall The survival period is 15.9 months. ^[5]

Temozolomide clinical trials:

Temozolomide Foreign Clinical Trials:

Newly diagnosed glioblastoma multiforme: 573 patients were randomized to receive temozolomide + local radiotherapy (n = 287) or monotherapy (n = 286). Patients in the temozolomide + topical radiotherapy group started taking temozolomide 75mg / m on the first day of radiotherapy, once a day for a total of 42 days (up to 49 days). Subsequently, temozolomide adjuvant therapy was started 4 weeks after the end of radiotherapy: a cycle of 28 days, taking medication on the 1st to 5th days of each cycle, 150-200mg / m daily for 6 cycles. Patients in the control group received radiotherapy only. Prevention of pneumocystis carinii pneumonia (PCP) during radiotherapy and combination therapy with temozolomide is required until the lymphocytopenia returns to <1 degree.

During follow-up, 161 (57%) of the 282 patients who received only radiotherapy and 62 (22%) of the 277 patients who received temozolomide plus radiotherapy received temozolomide again.

The overall survival hazard ratio (HR) was 1.59 (95% CI 1.33-1.91), and the time-series test p <0.0001 was beneficial to the temozolomide group. The 2-year survival rate of the temozolomide + radiotherapy group was higher than that of the control group (26% vs. 10%). Newly diagnosed patients with glioblastoma multiforme treated with concurrent chemoradiotherapy plus temozolomide adjuvant therapy have significantly improved overall survival compared with radiotherapy alone, and have statistical significance. (figure 1)

Figure 1 Kaplan-Meier curve for overall survival (intent-to-treat population, ITT)

Malignant glioma that recurs or progresses after routine treatment

The clinical efficacy data for patients with glioblastoma multiforme (Karnofsky performance status score 70) that relapse or progress after surgery or radiotherapy are from two clinical trials. One was an uncontrolled trial in 138 patients (29% had received chemotherapy); the other was in 225 patients (67% of patients had received nitrosourea-based chemotherapy) Randomized, controlled trials of temozolomide and procarbazine (methylbenzide). The primary endpoint of both trials was progression-free survival (PFS), judged by MRI scans or worsening neurological symptoms. In the uncontrolled trial, the 6-month PFS was 19%. The median PFS was 2.1 months, and the median overall survival time was 5.4 months. The objective response rate of the MRI scan was 8%.

In randomized, controlled studies, the 6-month progression-free survival PFS in the temozolomide group was significantly higher than that of the procarbazide group (21% vs. 8%, Chi-square test p = 0.008), and the median PFS was 2.89 months and 1.88 months ( Time series test p = 0.0063). The median survival times for the temozolomide group and the procarbazine group were 7.34 months and 5.66 months, respectively (p = 0.33 for the log-rank test). At 6 months, the survival rate of patients in the temozolomide group was significantly higher than that of the procarbazide group, which were 60% and 44%, respectively, and the chi-square test p = 0.019. Karnofsky's physical status has improved in patients who have previously received chemotherapy, which can reach 80 or more.

At the same time as the deterioration of physical status (KPS score remained above 60 or at least 30 decreased), the data on the time of deterioration of neurological symptoms were better in the temozolomide group than in the procarbazine group. For the median progression time of these endpoints, the temozolomide group was 0.7-2.1 months longer than the procarbazide group (p <0.01-0.03 for the time series test).

Anaplastic astrocytoma

A global, multicenter, prospective, non-randomized phase II trial evaluated the safety and effectiveness of oral temozolomide in patients with first-time recurrent anaplastic astrocytoma, with 46% of patients achieving progression-free survival of 6 months. The median progression-free survival was 5.4 months. The median overall survival time was 14.6 months. Based on a concentrated evaluation of the ITT population, the remission rate was 35%, with 13 CRs and 43 PRs. Including 43 cases of continuous remission, the remission rate was 61%. The 6-month event-free survival time in the ITT population reached 44%, and the median event-free survival time was 4.6 months, which was similar to the progression-free survival time. For populations suitable for histological examination, the effectiveness results were similar. Patients can improve and maintain their quality of life when they achieve objective radiological remissions or maintain progression-free status.

Temozolomide domestic clinical trials

The clinical trials conducted in China in 2005 were multicenter, open, randomized, and parallel controlled trials of positive drugs. A study comparing the efficacy and safety of temozolomide and stoxilastine in the treatment of glioblastoma or anaplastic astrocytoma that relapses or progresses after conventional treatment. A total of 144 subjects were enrolled in this study, 79 in the temozolomide group and 65 in the semustine group. The starting dose of temozolomide is 150 mg / m / day (for those who have received chemotherapy) or 200 mg / m / day (for those who have not received chemotherapy), given orally for 5 consecutive days, every 28 days as a treatment cycle; The initial dose is 150 mg / m / day, once a day, once every 28 days; the treatment period for both drugs is 2 to 6 months. By the time of treatment to June, the progression-free survival rates of the temozolomide group and the control group were 78.29% versus 55.08%, respectively; the overall clinical response rates (including complete and partial responses) were 45.83% versus 21.27%, respectively.

Tests have shown that temozolomide may be more effective in treating relapsed glioblastoma (GBM) and anaplastic astrocytoma (AA) than stemolastine. ^[4]