Diurnal lamotrigine plasma level fluctuations: clinical significance and indication of shorter half-life with chronic administration

For therapeutic monitoring of antiepileptic drugs (AEDs), morning trough levels (MTLs) are generally used. For specific questions like verification of breakthrough seizures or reported toxicity, however, other measures such as minimal and maximal concentrations (Cmin, Cmax) can be important and may require daily profiles. For clinical reasons, 20 daily profiles of lamotrigine (LTG) plasma levels were determined in nine patients. The results revealed fluctuations exceeding those expected from its elimination half-life (t1/2) of 22 h as reported in the literature. Patients on twice-daily regimens without pharmacokinetic interactions exhibited Cmin/Cmax ratios between 0.62 and 0.69. Fluctuations were smaller in those co-medicated with valproate, and reached a ratio of 0.55 in those co-medicated with phenobarbital. The Cmax was as much as 58% above the MTL. Therefore, verification of complaints indicating toxicity requires determination of drug levels when the symptoms are present. Our findings indicate that the t1/2 of LTG with chronic treatment is shorter than generally assumed, and suggest that a slow-release formulation could be helpful in achieving full seizure control in patients with a narrow individual therapeutic index for LTG.