ch 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 formulation result in comparable Cmax, Cmin, and AUC when the IV formulation is administered as a 15 minute infusion. This equivalence was demonstrated in a bioavailability study of 17 healthy adult volunteers, where levetiracetam 1500 mg IV, administered over 15 minutes, provided similar plasma concentrations at the end of infusion compared to those achieved at the Tmax of an equivalent oral dose. |
