Nonclassic Alkylating Agent
Temozolomide
CH3
H2N
N
N
N N
N
O
C
O
Trade Names
Temodar
Classification
Nonclassic alkylating agent
Category
Chemotherapy drug
Drug Manufacturer
Schering
Mechanism of Action
Imidazotetrazine analog that is structurally and functionally similar
to dacarbazine.
Cell cycle–nonspecific agent.
Metabolic activation to the reactive compound MTIC is required for
antitumor activity.
Although the precise mechanism of cytotoxicity is unclear, this drug
methylates guanine residues in DNA and inhibits DNA, RNA, and
protein synthesis. Does not cross-link DNA strands.
Mechanism of Resistance
Increased activity of DNA repair enzymes such as O6-alkylguanine DNA
alkyltransferase.
Absorption
Widely distributed in body tissues. Rapidly and completely absorbed with
an oral bioavailability approaching 100%. Maximum plasma concentrations
are reached within 1 hour after administration. Food reduces the rate and
extent of drug absorption.
Distribution
Because temozolomide is lipophilic, it crosses the blood-brain barrier.
Levels in brain and CSF are 30%–40% of those achieved in plasma.
Metabolism
Metabolized primarily by non-enzymatic hydrolysis at physiologic pH.
Undergoes conversion to the metabolite MTIC, which is further hydrolyzed
to AIC, a known intermediate in purine de novo synthesis, and methylhydrazine,
the presumed active alkylating species. The elimination half-life of
the drug is 2 hours. About 40%–50% of the parent drug is excreted in urine
within 6 hours of administration, and tubular secretion is the predominant
mechanism of renal excretion. No specific guidelines for drug dosing in the
setting of hepatic and/or renal dysfunction. However, dose modification
should be considered in patients with moderately severe hepatic and/or renal
dysfunction.
Indications
FDA-approved for refractory anaplastic astrocytomas at first relapse
following treatment with a nitrosourea and procarbazine-containing
regimen.
FDA-approved for newly diagnosed glioblastoma multiformae
(GBM) in combination with radiotherapy and then as maintenance
treatment.
Metastatic melanoma.
DosageRange
Usual dose is 150 mg/m 2 PO daily for 5 days every 28 days.
Dose is adjusted to nadir neutrophil and platelet counts. If nadir of
ANC is acceptable, the dose may be increased to 200 mg/m 2 PO
daily for 5 days. If ANC falls below acceptable levels during any cycle,
the next dose should be reduced by 50 mg/m 2 PO daily.
Temozolomide is given at 75 mg/m 2 PO daily for 42 days along
with focal radiotherapy (60 Gy in 30 fractions) for newly diagnosed
GBM. During the maintenance phase, which is started 4 weeks after
completion of the combined modality therapy, temozolomide is given
on cycle 1 at 150 mg/m 2 PO daily for five days followed by 23 days
without treatment. For cycles 2–6, the dose of temozolomide may be
escalated to 200 mg/m 2 if tolerated.
Drug Interactions
None known.
Special Considerations
Temozolomide is a moderately emetogenic agent. Aggressive use of
antiemetics prior to drug administration is required to decrease the
risk of nausea and vomiting.
Patients should be warned to avoid sun exposure for several days
after drug treatment.
Use with caution in elderly patients (age _65) as they are at
increased risk for myelosuppression.
Patients should be monitored closely for the development of PCP,
and those receiving temozolomide and radiotherapy require PCP
prophylaxis.
Pregnancy category D. Breast-feeding should be discontinued.
Toxicity 1
Myelosuppression. Dose-limiting toxicity. Leukopenia and thrombocytopenia
are commonly observed.
Toxicity 2
Nausea and vomiting. Mild to moderate, usually occurring within
1–3 hours and lasting for up to 12 hours. Aggressive antiemetic therapy
strongly recommended.
Toxicity 3
Headache and fatigue.
Toxicity 4
Mild elevation in hepatic transaminases.
Toxicity 5
Photosensitivity.
Toxicity 6
Teratogenic, mutagenic, and carcinogenic.