Temozolomide is an oral alkylating agent, which belongs to the class of drugs called imidazotetrazines. It exerts its anticancer effects by alkylating DNA, which results in DNA damage and ultimately leads to cell death. Specifically, temozolomide methylates the O6 position of guanine in DNA, leading to mispairing with thymine, DNA strand breaks, and inhibition of DNA replication. This damage is more pronounced in rapidly dividing cancer cells.

1. Pharmacokinetics

• Absorption: Temozolomide is rapidly absorbed after oral administration. Peak plasma concentrations are typically reached within 1-2 hours. It has a bioavailability of approximately 100%, meaning it is almost completely absorbed into the bloodstream.
• Distribution: Temozolomide is widely distributed throughout the body, including the central nervous system (CNS), which is crucial for treating brain tumors.
• Metabolism: Temozolomide is metabolized in the liver by cytochrome P450 enzymes, specifically CYP1A2. It is converted to its active form, MTIC (methyltriazeno imidazole carboxamide).
• Elimination: The drug is primarily excreted in the urine. The half-life of temozolomide is about 1.8 hours, and its active metabolite (MTIC) has a half-life of approximately 2-3 hours.

2. Dosage and Administration

• For Newly Diagnosed Glioblastoma Multiforme (GBM):
  • Initial Dose: 75 mg/m² once daily for 42 days, in combination with radiotherapy.
  • Consolidation Phase: After radiation, 150 mg/m² once daily for 5 days of each 28-day cycle, for up to 6 cycles.
• For Recurrent Glioblastoma Multiforme:
  • Initial Dose: 150 mg/m² once daily for 5 days of each 28-day cycle. The dose can be escalated up to 200 mg/m² if well tolerated, but should not exceed 200 mg/m² per day.
• For Anaplastic Astrocytoma:
  • Initial Dose: 150 mg/m² once daily for 5 days in a 28-day cycle, with a dose escalation in subsequent cycles as needed.

.   Administration Instructions:

• Temozolomide should be taken on an empty stomach, either one hour before or two hours after a meal, to maximize absorption.
• The capsules should be swallowed whole with water and should not be opened or crushed.

3. Contraindications

• Hypersensitivity to temozolomide or any of its components.
• Pregnancy: Temozolomide is classified as a Category D drug (positive evidence of risk). It should not be used during pregnancy unless the potential benefit justifies the risk to the fetus.

4. Warnings and Precautions

• Myelosuppression: Temozolomide can cause bone marrow suppression, leading to neutropenia, thrombocytopenia, and anemia. Blood counts should be monitored regularly.
• Infections: Patients receiving temozolomide may be at increased risk for infections due to the suppression of white blood cells. Use with caution in patients with pre-existing infections.
• Nausea and Vomiting: Common side effects include nausea and vomiting. Antiemetic therapy may be required.
• Liver Dysfunction: Caution should be used in patients with hepatic impairment, as the drug is metabolized in the liver.
• Secondary Malignancies: There is a potential risk for the development of secondary cancers, such as leukemia, especially in patients receiving long-term treatment.

5. Adverse Reactions

Common Side Effects:

• Hematologic: Leukopenia, thrombocytopenia, anemia, neutropenia.
• Gastrointestinal: Nausea, vomiting, loss of appetite, constipation, diarrhea.
• Neurological: Headache, dizziness, somnolence, confusion.
• General: Fatigue, fever, chills.

Serious Adverse Effects:

• Infections due to immune suppression.
• Liver Toxicity: Hepatic failure, liver enzyme abnormalities.
• Pulmonary Toxicity: Pneumonitis and other lung-related side effects may occur, especially with concurrent treatments.
• Severe Myelosuppression: May require dose adjustments or discontinuation.

6. Drug Interactions

• CYP1A2 Inhibitors (e.g., ciprofloxacin, fluvoxamine): May increase temozolomide levels due to inhibition of its metabolism.
• CYP1A2 Inducers (e.g., rifampin): May decrease temozolomide levels by increasing its metabolism.
• Other Chemotherapy Agents: Temozolomide may be used in combination with other chemotherapeutic agents like bevacizumab. However, the risks of increased myelosuppression should be monitored.

7. Monitoring and Follow-up

• Blood Counts: Regular complete blood count (CBC) monitoring for signs of bone marrow suppression is essential, especially during the initial cycles.
• Liver Function Tests: Liver enzymes should be monitored regularly to detect any hepatic toxicity.
• Clinical Monitoring: Monitor for signs of infection, gastrointestinal symptoms (such as nausea and vomiting), and any neurologic or pulmonary complications.

8. Pregnancy and Lactation

• Pregnancy: Temozolomide can cause fetal harm and should not be used during pregnancy unless absolutely necessary. If used, the patient should be fully informed of the potential risks.
• Lactation: It is unknown whether temozolomide is excreted in human breast milk. Given the potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment with temozolomide.

9. Storage

• Storage Conditions: Store at room temperature, 20°C to 25°C (68°F to 77°F). Keep the medication in its original container to protect it from moisture and light.