Temozolomide

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O⁶ position of guanine with additional alkylation also occurring at the N⁷ position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

Temozolomide is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl(triazen-1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5amino-imidazole4carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA mainly at the O⁶ and N⁷ positions of guanine. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is ~ 2.4% and 23%, respectively. In vivo, the t_½ of MTIC was similar to that of temozolomide, 1.8 hr.

In an open-label, two-way crossover bioequivalence study of the pharmacokinetics of oral and intravenous temozolomide in patients with primary CNS malignancies, temozolomide 2.5 mg/ml powder for solution for infusion administered over 90 minutes was found to be bioequivalent for C_max and AUC of temozolomide and MTIC as compared to temozolomide hard capsules, following administration of 150 mg/m² dose. Mean C_max values for temozolomide and MTIC were 7.4 μg/ml and 320 ng/ml, respectively, following 90 minute intravenous infusion. Mean AUC_(0→∞) values for temozolomide and MTIC were 25 μg•h/ml and 1,004 ng•h/ml, respectively.

Absorption

After oral administration to adult patients, temozolomide is absorbed rapidly, with peak concentrations reached as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral administration of ¹⁴C-labelled temozolomide, mean faecal excretion of ¹⁴C over 7 days post-dose was 0.8% indicating complete absorption.

Distribution

Temozolomide demonstrates low protein binding (10% to 20%), and thus it is not expected to interact with highly protein-bound substances.

PET studies in humans and preclinical data suggest that temozolomide crosses the blood-brain barrier rapidly and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on AUC of temozolomide was approximately 30% of that in plasma, which is consistent with animal data.

Elimination

The half-life (t_1/2) in plasma is approximately 1.8 hours. The major route of ¹⁴C elimination is renal. Following oral administration, approximately 5% to 10% of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of temozolomide revealed that plasma temozolomide clearance was independent of age, renal function or tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose (MTD) was 1,000 mg/m² per cycle both in children and in adults.

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system, testes, the gastrointestinal tract and, at higher doses, which were lethal to 60% to 100% of rats and dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility, except for adverse events on the male reproductive system and retinal degeneration. However, because the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect has been observed in clinical studies, this finding was not considered to have clinical relevance.

Temozolomide is an embryotoxic, teratogenic and genotoxic alkylating agent. Temozolomide is more toxic to the rat and dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs. Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of temozolomide, with the occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome aberration tests showed a positive mutagenicity response.