Clinical Pharmacology Unit, University of Pavia, Pavia, Italy The National Center for Epilepsy, Sandvika, Norway
The pharmacokinetic properties of a drug are the primary determinant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older‐generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non‐linear kinetics; carbamazepine and valproic acid have relatively short half‐lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new‐generation AEDs offer a number of pharmacokinetic advantages, particularly in terms of reduced inter‐patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half‐life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice‐daily dosing regimen is adequate to produce the desired response.