Abstracts

Rationale: Levetiracetam (LEV) is eliminated by renal excretion and, to a lesser extent, by hydrolysis to the inactive metabolite L057. Because the cytochrome P450 enzyme system plays no important role in LEV metabolism, enzyme inducing antiepileptic drugs (AEDs) have been considered not to influence significantly LEV clearance. However, some observations suggest that plasma LEV levels are decreased by enzyme inducing comedication. The aim of the present study was to compare LEV pharmacokinetics in subjects receiving enzyme inducing AEDs (EIAED group) and subjects not receiving enzyme inducers (control group). Methods: Fifteen subjects receiving chronic treatment with carbamazepine, phenytoin or phenobarbital alone or in combination therapy (EIAED group) and 15 controls matched for age, gender and body weight gave their consent to participate. Subjects receiving enzyme inhibiting comedications such as valproic acid and felbamate, and subjects with altered renal or hepatic function were excluded. Each subjects received after an overnight fast a single oral 1000 mg dose of LEV, and blood and urine samples were collected at regular intervals for up to 24 h. HPLC methods was used to determine LEV concentrations in plasma and LEV and ucb L057 concentrations in urine. Pharmacokinetic parameters were calculated by model independent-analysis and compared between groups by using the Student t-test or Mann-Whitney test, as appropriate. Results: Compared with controls, subjects in the EIAED group had higher LEV apparent oral clearance (CL/F) values (1.17 0.3 vs 0.93 0.22 mL/min/Kg, means SD, p<0.05) and shorter LEV half-lives (6.1 1.0 vs 7.3 1.5 h, p<0.05). The amount of LEV excreted in urine as unchanged drug and as ucb L057 did not differ significantly between the two groups. Conclusions: Enzyme inducing AEDs cause a moderate increase in LEV clearance, an effect which is associated with a modest shortening of LEV half-life. The mechanism(s) responsible for this interaction are unclear.