abolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) which is known to be an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. About 38% of the administered temozolomide total radioactive dose is recovered over 7 days; 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is as unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m 2 .
Special Populations: Age Population pharmacokinetic analysis indicates that age (range 19 to 78 years) has no influence on the pharmacokinetics of temozolomide. In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia in the first cycle of therapy than patients under 70 years of age (see PRECAUTIONS ).
Gender Population pharmacokinetic analysis indicates that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men. Women have higher incidences of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than men (see ADVERSE REACTIONS ).
Race The effect of race on the pharmacokinetics of temozolomide has not been studied.
Tobacco Use Population pharmacokinetic analysis indicates that the oral clearance of temozolomide is similar in smokers and nonsmokers.
Creatinine Clearance Population pharmacokinetic analysis indicates that creatinine clearance over the range of 36-130 mL/min/m 2 has no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr < 36 mL/min/m 2 ). Caution should be exercised when TEMODAR Capsules are administered to patients with severe renal impairment. TEMODAR has not been studied in patients on dialysis.
Hepatically Impaired Patients In a pharmacokinetic study, the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child's-Pugh Class I - II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment.
Drug-Drug Interactions In a multiple-dose study, administration of TEMODAR Capsules with ranitidine did not change the C max or AUC values for temozolomide or MTIC.
Population analysis indicates that administration of valproic acid decreases the clearance of temozolomide by about 5% (see PRECAUTIONS ).
Population analysis failed to demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H 2 -receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.
CLINICAL STUDIES
Newly Diagnosed Glioblastoma Multiforme Five hundred and seventy-three patients were randomized to receive either TEMODAR (TMZ) + Radiotherapy (RT) (n=287) or RT alone (n=286). Patients in the TEMODAR + RT arm received concomitant TEMODAR (75 mg/m 2 ) once daily, starting the first day of RT until the l |
