t to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the O6 and N7 positions of guanine.
12.3 PharmacokineticsAbsorption:
Temozolomide is rapidly and completely absorbed after oral administration with a peak plasma concentration (Cmax ) achieved in a median Tmax of 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and median Tmax increased by 2-fold (from 1–2.25 hours) when temozolomide was administered after a modified high-fat breakfast.
A pharmacokinetic study comparing oral and intravenous temozolomide in 19 patients with primary CNS malignancies showed that 150 mg/m2 TEMODAR for injection administered over 90 minutes is bioequivalent to 150 mg/m2 TEMODAR oral capsules with respect to both Cmax and AUC of temozolomide and MTIC. Following a single 90-minute intravenous infusion of 150 mg/m2 , the geometric mean Cmax values for temozolomide and MTIC were 7.3 mcg/mL and 276 ng/mL, respectively. Following a single oral dose of 150 mg/m2 , the geometric mean Cmax values for temozolomide and MTIC were 7.5 mcg/mL and 282 ng/mL, respectively. Following a single 90-minute intravenous infusion of 150 mg/m2 , the geometric mean AUC values for temozolomide and MTIC were 24.6 mcg∙hr/mL and 891 ng∙hr/mL, respectively. Following a single oral dose of 150 mg/m2 , the geometric mean AUC values for temozolomide and MTIC were 23.4 mcg∙hr/mL and 864 ng∙hr/mL, respectively.
Distribution:
Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.
Metabolism and Elimination:
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, MTIC and to temozolomide acid metabolite. 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.
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 |
