The ideal pharmacokinetic properties of an antiepileptic drug: how close does levetiracetam come?
The pharmacokinetic properties of a drug are the primary deter-minant 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 num-ber 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.
Perucca
Emilio
E
Clinical Pharmacology Unit, University of Pavia, Pavia, Italy. perucca@unipv.it
Johannessen
Svein I
SI
D000085:Acetates / Q000493:pharmacokinetics / Q000627:therapeutic use; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D003509:Cyclohexanecarboxylic Acids; D004347:Drug Interactions; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism; D000078328:Felbamate; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077206:Gabapentin; D006207:Half-Life; D006801:Humans; D007555:Isoxazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077213:Lamotrigine; D000077287:Levetiracetam; D009557:Nipecotic Acids / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078330:Oxcarbazepine; D048448:Phenylcarbamates; D010889:Piracetam / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078308:Tiagabine; D000077236:Topiramate; D014227:Triazines / Q000493:pharmacokinetics / Q000627:therapeutic use; D020888:Vigabatrin / Q000493:pharmacokinetics / Q000627:therapeutic use; D000078305:Zonisamide; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D007555:Isoxazoles; D009557:Nipecotic Acids; D048448:Phenylcarbamates; D011409:Propylene Glycols; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D000077287:Levetiracetam; D000078305:Zonisamide; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D020888:Vigabatrin; D000077213:Lamotrigine; D000078330:Oxcarbazepine; D000078328:Felbamate; D000078308:Tiagabine; D010889:Piracetam