Effects of antiepileptic comedication on levetiracetam pharmacokinetics: a pooled analysis of data from randomized adjunctive therapy trials.
OBJECTIVE
To assess the influence of commonly used antiepileptic drugs (AEDs) on levetiracetam pharmacokinetics at steady state.


METHODS
Plasma levetiracetam concentrations at steady state were determined by capillary gas chromatography in 590 epilepsy patients included in phase III trials and treated with doses of 1000-4000 mg per day in two divided daily doses. The data were pooled and kinetic parameters estimated by repeated measurement covariance analysis on log-transformed dose-adjusted concentrations (regression line as function of time elapsed since last dose).


RESULTS
Estimated pharmacokinetic values, normalized to a dose of 1 mgkg(-1) b.i.d., were: concentration at 1h (C(1h)) 2.1 microgram ml(-1), concentration at 12h (C(12h)) 0.8 microgram ml(-1), area under the curve from 0 to 12h (AUC(0-12h)) 17.1 microgram ml(-1)h, half-life (t(1/2)) 8.1h, and apparent oral clearance (CL/F) 0.97 mlmin(-1)kg(-1). Parameters were similar between genders and among dosage subgroups. Compared with patients receiving comedication not considered to affect drug metabolizing enzymes (gabapentin, lamotrigine, vigabatrin), levetiracetam concentrations and t(1/2) tended to be lower in patients receiving enzyme-inducing AEDs (carbamazepine, phenytoin, phenobarbital, primidone) and higher in patients receiving valproic acid, but the differences were modest.


CONCLUSIONS
Estimated parameters were dose independent, comparable to those from smaller scale studies and not affected to any major extent by gender or comedication with other AEDs. Based on this, no need is anticipated for adjusting levetiracetam dosage according to type of concomitantly prescribed AEDs.
Perucca
E
E
Department of Internal Medicine and Therapeutics, Clinical Pharmacology Unit, University of Pavia, Piazza Botta 10, 27100, Pavia, Italy. perucca@unipv.it
Gidal
B E
BE
Baltès
Eugène
E
D000328:Adult; D000368:Aged; D000465:Algorithms; D000927:Anticonvulsants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010889:Piracetam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D012727:Sex Characteristics
D000927:Anticonvulsants; D000077287:Levetiracetam; D010889:Piracetam