LAMOTRIGINE CLINICAL PHARMACOKINETICS

Lamotrigine is a new antiepileptic agent chemically unrelated to any e stablished drugs in use. The drug can be estimated in biological fluid s by high performance liquid chromatography and immunoassays. It is ra pidly absorbed, reaching peak concentrations within about 3 hours post dose. The bioavailability of the oral formulation is about 98%. The ar ea under the plasma concentration-time curve indicates dose-linear pha rmacokinetics. The degree of plasma protein binding is 56%. Saliva con centrations are 46% of the plasma concentration. The concentration of lamotrigine in the brain is similar to the total concentration in the plasma. Lamotrigine exhibits first-oiler linear kinetics during long t erm administration. 43 to 87% of a dose is recovered in the urine, pre dominantly as glucuronide metabolites. Mean half-lives of lamotrigine in healthy volunteers (single and multiple doses) as well as in epilep tic patients receiving lamotrigine monotherapy range from 22.8 to 37.4 hours. Enzyme-inducing antiepileptic drugs such as phenytoin, phenoba rbital (phenobarbitone) or carbamazepine reduce the half-life of lamot rigine (to mean values of 13.5 to 15 hours), whereas valproic acid inc reases the half-life of the drug (to mean values of 48.3 to 59 hours). Lamotrigine itself does not influence the plasma concentrations of co ncomitant antiepileptic drugs, except for causing an increase in conce ntrations of carbamezepine-10,11-epoxide, the main metabolite of carba mazepine. Other observations indicate that the interaction of carbamaz epine and lamotrigine may be primarily pharmacodynamic rather than pha rmacokinetic. Usual dosages of lamotrigine range from 50 to 400 mg/day depending on an enzyme-inducing or -inhibiting comedication. Therapeu tic plasma concentrations of the drug are not known, but a putative th erapeutic range of 1 to 4 mg/L has been proposed. Some patients have t olerated concentrations >10 mg/L with benefit and without clinical tox icity. The value of measuring the concentrations of lamotrigine in hel ping to optimise the dosage or reduce the likelihood of adverse effect s has not been established. Safety data from several large studies ind icate that the incidence of adverse effects of the drug is low and tha t unwanted effects are reversible.