es 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.
Excretion:
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 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/m2. Temozolomide is rapidly eliminated, with a mean elimination half-life of 1.8 hours, and exhibits linear kinetics over the therapeutic dosing range of 75 to 250 mg/m2/day.
Effect of Age:
A population pharmacokinetic analysis indicated that age (range: 19–78 years) has no influence on the pharmacokinetics of temozolomide.
Effect of Gender:
A population pharmacokinetic analysis indicated that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men.
Effect of Race:
The effect of race on the pharmacokinetics of temozolomide has not been studied.
Tobacco Use:
A population pharmacokinetic analysis indicated that the oral clearance of temozolomide is similar in smokers and nonsmokers.
Effect of Renal Impairment:
A population pharmacokinetic analysis indicated that creatinine clearance over the range of 36 to 130 mL/min/m2 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/m2). Caution should be exercised when TEMODAR is administered to patients with severe renal impairment [see Use in Special Populations (8.6)]. TEMODAR has not been studied in patients on dialysis.
Effect of Hepatic Impairment:
A study showed that the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child-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 [see Use in Special Populations (8.7)].
Effect of Other Drugs on Temozolomide Pharmacokinetics:
In a multiple-dose study, administration of TEMODAR Capsules with ranitidine did not change the Cmax or AUC values for temozolomide or MTIC.
A population analysis indicated that administration of valproic acid decreases the clearance of temozolomide by about 5% [see Drug Interactions (7)].
A population analysis did not demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Temozolomide is carcinogenic in rats at doses less than the maximum recommended human dose. Temozolomide induced mammary carcinomas in both males and females at doses 0.13 to 0.63 times the maximum human dose (25–125 mg/m2) when administered orally on 5 consecutive days every 28 days for 6 cycles. Temozolomide also induced fibrosarcomas of the heart, eye, seminal vesicles, salivary glands, abdominal cavity, uterus, and prostate, carcinomas of the seminal vesicles, schwannomas of the heart, optic nerve, and harderian gland, and |
