TEMODAL 180 MG

Indications

• Gli

Mechanism of action

Temozolomide is converted in vivo to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC), which then generates a highly reactive methyl diazonium cation. This cation methylates DNA at specific positions, predominantly at the N7 position of guanine and the O6 position of guanine. The methylation leads to DNA damage that triggers futile repair cycles, resulting in cell death. Glioblastomas typically have a higher pH than normal tissue, favoring the activation of temozolomide within the tumor microenvironment.

Pharmacodynamics

As a prodrug, temozolomide requires nonenzymatic hydrolysis to exert its effects. The resulting alkylation of DNA bases leads to significant DNA damage and triggers cellular apoptosis. Temozolomide can cause myelosuppression, which may be exacerbated in female and older patients. Monitoring of absolute neutrophil count (ANC) and platelet levels is crucial before and during treatment, as severe myelosuppression and secondary malignancies, including myeloid leukemia, have been reported.

Pharmacokinetics

Temozolomide is well-absorbed after oral administration, with a bioavailability of approximately 100%. It is distributed widely throughout the body, including the central nervous system, due to its lipophilicity. The drug undergoes nonenzymatic decomposition at physiological pH to its active form. The elimination half-life of temozolomide ranges from 1.5 to 2 hours, with renal excretion being the primary route of elimination for the drug and its metabolites. Hepatic function must be monitored, as hepatotoxicity has been reported in some patients.

Contra-indications

• Hypersensitivity to temozolomide or any of its components
• Pregnancy
• Severe myelosuppression

Adverse effects

• Nausea
• Vomiting
• Myelosuppression
• Fatigue
• Headache
• Constipation
• Dizziness
• Pneumocystis pneumonia
• Hepatotoxicity
• Myelodysplastic syndrome
• Secondary malignancies, including myeloid leukemia

Interactions

• Concomitant use with other myelosuppressive agents may increase the risk of severe myelosuppression
• Use with caution in patients receiving radiotherapy
• Prophylactic antibiotics may be needed for opportunistic infections

Precautions

• Monitor complete blood counts regularly during treatment
• Assess liver function tests before and during treatment
• Consider prophylaxis against Pneumocystis pneumonia in at-risk patients
• Patients must have an absolute neutrophil count (ANC) of ≥1.5 x 10^9/L and a platelet count of ≥100 x 10^9/L before starting therapy

Pregnancy

Temozolomide is contraindicated in pregnancy due to potential fetal harm.

Breast-feeding

Use with caution as it is not known whether temozolomide is excreted in human milk.

Storage

Store in a cool, dry place, protected from light. Keep out of reach of children.

Formulations

• Capsules (various strengths)
• Injection for intravenous use

Mechanism of action

Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T_reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future.

Pharmacodynamics

Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH _in vivo_ to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10⁹/L and a platelet count of ≥100 x 10⁹/L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, respectively.