Lamotrigine Clinical Pharmacokinetics

Summary

Lamotrigine is a new antiepileptic agent chemically unrelated to any established drugs in use. The drug can be estimated in biological fluids by high performance liquid chromatography and immunoassays. It is rapidly absorbed, reaching peak concentrations within about 3 hours postdose. The bioavailability of the oral formulation is about 98%. The area under the plasma concentration-time curve indicates dose-linear pharmacokinetics. The degree of plasma protein binding is 56%. Saliva concentrations 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-order linear kinetics during long term administration. 43 to 87% of a dose is recovered in the urine, predominantly as glucuronide metabolites. Mean half-lives of lamotrigine in healthy volunteers (single and multiple doses) as well as in epileptic patients receiving lamotrigine monotherapy range from 22.8 to 37.4 hours. Enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital (phenobarbitone) or carbamazepine reduce the half-life of lamotrigine (to mean values of 13.5 to 15 hours), whereas valproic acid increases the half-life of the drug (to mean values of 48.3 to 59 hours). Lamotrigine itself does not influence the plasma concentrations of concomitant antiepileptic drugs, except for causing an increase in concentrations of carbamazepine-10,11-epoxide, the main metabolite of carbamazepine. Other observations indicate that the interaction of carbamazepine and lamotrigine may be primarily pharmacodynamic rather than pharmacokinetic.

Usual dosages of lamotrigine range from 50 to 400 mg/day depending on an enzyme-inducing or -inhibiting comedication. Therapeutic plasma concentrations of the drug are not known, but a putative therapeutic range of 1 to 4 mg/L has been proposed. Some patients have tolerated concentrations >10 mg/L with benefit and without clinical toxicity. The value of measuring the concentrations of lamotrigine in helping to optimise the dosage or reduce the likelihood of adverse effects has not been established. Safety data from several large studies indicate that the incidence of adverse effects of the drug is low and that unwanted effects are reversible.