Pharmacotherapeutics of epilepsy: use of lamotrigine and expectations for lamotrigine extended release

The goal in managing patients with epilepsy is complete seizure freedom. Pharmacotherapeutic management of epilepsy is complicated by multiple syndromes, inter-individual differences in drug sensitivities, inter-individual differences in drug disposition, and drug interactions. Most anti-epileptic drugs (AEDs) have a therapeutic window with only a 2- to 3-fold concentration range. Extended release formulations offer advantages over their immediate release counter parts with less fluctuation in the serum concentration vs time curve and improved compliance. However, missed doses are more likely to result in prolonged “sub-therapeutic serum concentrations”. Best clinical outcome may sometimes require twice daily dosing of extended release formulations even though approved for once daily dosing, as this optimally balances pharmacokinetics against compliance. Lamotrigine (LTG) is a broad spectrum AED with efficacy in partial and generalized epilepsy syndromes and good tolerability. Its metabolism is affected by co-medications which may be inducing, neutral or inhibiting of hepatic glucuronidation. Furthermore, though the average half-life in monotherapy is about 24 hours, there is a large inter-individual variation that may, including the extremes, approach a range of 10-fold. LTG-XR is expected to decrease fluctuation of serum concentration in the presence of hepatic inducing or neutral drugs. However, optimal clinical benefit in some patients may require twice daily dosing when metabolism is rapid.