Abstracts

Rationale: Lamotrigine (LTG) is one of the most commonly used antiepileptic drugs. It is reported to have linear kinetics, so that the elimination rate is linearly proportional to the blood concentration, the half-life is constant, and a percent change in dose is accompanied by an equal percent change in serum concentration. We encountered a number of patients in whom LTG serum concentration increased dramatically in response to a minor change or even no change in LTG dose. Methods: We identified patients who developed clinical LTG overdose toxicity with LTG serum concentrations greater than 20 mcg/ml, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity. Results: 26 patients had an episode of LTG toxicity with levels higher than 20 mcg/ml. The peak serum concentration varied from 21.1 to 40.3 mcg/ml (mean 29.2). The increase in level was explained in 6 patients (post-delivery, increase in valproate dose, increase in lamotrigine dose, irregular compliance). However, 20 patients developed an increase in LTG level that was not explained by change in dose, or that was disproportionate to the increase in LTG dose. In these patients the change was also not explained by an interaction. Examples include a 57 year old woman who had a stable LTG level of 18-20 mcg/ml at a dose of 600 mg per day. After the dose was increased by 25 mg/day (4% change in dose), her level rose to 40.3 mg/ml (99.5% increase in level), with associated clinical toxicity (Figure 1). A 66 year old woman had an LTG level of 16.2 on a dose of 600 mg per day. Her level rose to 37.6 (132% increase) without a change in dose, with vomiting and diarrhea, then came back down spontaneously (Figure 2). Conclusions: Spikes in LTG levels and associated clinical toxicity may occur unexpectedly in some individuals, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been close to 15-20 mcg/ml.