Sign Out
Pharmacology: Pharmacodynamics: The active substance, Levetiracetam is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Mechanism of action: The mechanism of action of Levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products.
Pharmacodynamics effects: Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalized seizures without having pro-convulsant effect. The primary metabolite is inactive.
In man, activity in both partial and generalized epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum of the preclinical pharmacological profile.
Pharmacokinetics: Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear and time-independent with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.
Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of Levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of Levetiracetam.
A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours post-dose for oral solution formulation).
Adults and adolescent: Absorption: Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100%. Peak plasma concentrations (Cmax) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule. Peak concentrations (Cmax) are typically 31 and 43 μg/ml following a single 1,000 mg dose and repeated 1,000 mg b.i.d. dose, respectively. The extent of absorption is dose-independent and is not altered by food.
Distribution: No tissue distribution data are available in humans. Neither Levetiracetam nor its primary metabolite is significantly bound to plasma proteins (< 10%). The volume of distribution of Levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.
Biotransformation: Levetiracetam is not extensively metabolized in humans. The major metabolic pathway (24% of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P 450 isoforms.
Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other one by opening of the pyrrolidone ring (0.9% of the dose).
Other unidentified components accounted only for 0.6% of the dose.
No enantiomeric interconversion was evidenced in vivo for neither Levetiracetam nor its primary metabolite.
In vitro, Levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGTIA1 and UGTIA6) and epoxide hydroxylase activities in addition, Levetiracetam does not affect the in vitro glucuronidation of valproic acid.
In human hepatocytes in culture, Levetiracetam had little or no effect on ethinylestradiol conjugation or CYP1A1/2. Levetiracetam caused mild induction of CYP2B6 and CYP3A4 at high concentrations (680 μg/ml), however at concentrations approximating to the Cmax following a repeated 1500mg twice daily dose, the effects were not considered to be biologically relevant. Therefore, the interaction of LEVETIRACETAM with other substances, or vice versa, is unlikely.
Elimination: The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95% of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3% of the dose.
The cumulative urinary excretion of Levetiracetam and its primary metabolite accounted for 66% and 24% of the close, respectively during the first 48 hours. The renal clearance of Levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that Levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.
Elderly: In the elderly, the half-life is increased by about 40% (10 to 11 hours). This is related to the decrease in renal function in this population.
Children (4 to 12 years): Following single dose administration (20 mg/kg) to epileptic children, the half-life of Levetiracetam was 6.0 hours. The apparent body clearance was 1.43 ml/min/kg. Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), Levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours.
The apparent body clearance was 1.1 ml/min/kg.
Infants and children (1 month to 4 years): Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to epileptic children (1 month to 4 years), Levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).
Renal impairment: The apparent body clearance of both Levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of LEVETIRACETAM based on creatinine clearance in patients with moderate and severe renal impairment.
In anuric end-stage renal disease subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.
The fractional removal of Levetiracetam was 51% during a typical 4-hour dialysis session.
Hepatic impairment: In subjects with mild (Child-Pugh B) hepatic impairment, the pharmacokinetics of Levetiracetam was unchanged. In subjects with severe hepatic impairment (Child-Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted for most of the decrease.
No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50% reduction of the daily maintenance dose is recommended when the creatinine clearance is <60 ml/min/1.73m2.
