Clinical pharmacokinetics of levetiracetam

Abstract

Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of levetiracetam are highly favourable and make its clinical use simple and straightforward.