tered dose is metabolized via enzymatic hydrolysis of the acetamide group, producing a pharmacologically inactive carboxylic acid metabolite, ucb L057. Two minor metabolites produced via hydroxylation (2% of administered dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of administered dose) have also been identified. Metabolism is not dependent on hepatic cytochrome P450 isoenzymes (CYP) , although research has identified that minor CYP metabolism may exist. Levetiracetam is excreted renally via glomerular filtration with subsequent partial tubular reabsorption; approximately 66% of the administered dose is eliminated unchanged. Total body clearance is 0.96 mL/kg/minute and renal clearance is 0.6 mL/kg/minute in adults. The metabolite ucb L057 is excreted via glomerular filtration and active tubular secretion with a renal clearance of 4 mL/kg/minute. Levetiracetam plasma half-life in adults is about 6—8 hours for all dosage forms. The pharmacokinetics of levetiracetam are linear and time-invariant, with low intra- and inter-patient variability.
Affected cytochrome P450 isoenzymes: none
Oral Route
Bioavailabillty of immediate-release and extended-release formulations is similar. Administration of levetiracetam with food does not affect overall bioavailability, but prolongs Tmax and alters Cmax.
Immediate-release formulations
Levetiracetam fast-melting tablets (Spritam) disintegrate in a mean time of 11 seconds (range, 2—27 seconds), when taken with a small sip of liquid, resulting in small particles that may be swallowed. Absorption of immediate-release (IR) levetiracetam is rapid, with peak plasma concentrations occurring approximately 1 hour after oral administration under fasting conditions in both pediatric and adult patients. Oral bioavailability of the IR tablets is 100%; IR tablets and oral solution are bioequivalent. In addition, fast-melting tablets (Spritam) have been shown to have equivalent rate and extent of absorption to immediate-release levetiracetam tablets. Food does not affect the extent of absorption, but decreases Cmax by 20—36% and delays Tmax by 1.5—3.4 hours. The pharmacokinetics are linear and dose-proportional over a dosage range of 500—5000 mg/day in adult patients. Steady state is achieved after 2 days of twice-daily dosing.
Extended-release formulations
Absorption of the extended-release (ER) tablets is slower, with peak plasma concentrations occurring approximately 4 hours after oral administration. Oral bioavailability of the ER tablets is nearly 100%. Single administration of equivalent daily doses (e.g., two 500 mg ER tablets once daily compared to one 500 mg IR tablet twice daily) produces a comparable Cmax and AUC under fasting conditions to those of IR tablets. After multiple dose administration, AUC is similar between the 2 dosage forms; however, Cmax and Cmin are 17% and 26% lower, respectively, with administration of the ER tablets compared to the IR tablets. Intake of a high fat, high calorie breakfast before ER tablet administration results in a higher Cmax and longer mean Tmax; Tmax is approximately 2 hours longer when administered with food. The pharmacokinetics of ER levetiracetam are linear and dose-proportional over a dosage range of 1000—3000 mg/day in adult patients.
Intravenous Route
Levetiracetam injection and immediate-release oral formulations are bioequivalent. Equivalent doses of each formul |
