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Correlating lamotrigine serum concentrations with tolerability in patients with epilepsy

From the Comprehensive Epilepsy Center (Drs. Hirsch, Bazil, Adams, Resor, and Morrell, D. Weintraub, H. T. Spencer, M. Hager, and T. Straka), Department of Neurology, and Department of Biostatistics (Dr. Du, R. Buchsbaum), Mailman School of Public Health, Columbia University, New York, NY.

Address correspondence and reprint requests to Dr. L.J. Hirsch, Comprehensive Epilepsy Center, Department of Neurology, Columbia University, 710 W. 168 St., Box NI-135, New York, NY 10032; e-mail: ljh3{at}columbia.edu

Objective: To correlate lamotrigine (LTG) serum concentrations (levels) with tolerability in patients with epilepsy.

Methods: The charts of 811 outpatients with epilepsy who had received LTG and were seen at the Columbia Comprehensive Epilepsy Center after January 1, 2000, were reviewed. Data gathered included levels, dosage, duration of use, concomitant antiepileptic drugs (AEDs), clinical toxicity, specific side effects, and efficacy. Rates of toxicity, specific side effects, and efficacy were calculated and correlated with serum levels.

Results: In total, 3,731 LTG levels were recorded. A regimen was categorized as toxic if the patient experienced side effects that led to a dosage change or discontinuation of LTG. Of 3,919 AED regimens, 9.4% were toxic and 30.7% of patients had at least one toxic regimen. Toxicity increased with increasing LTG levels (p < 0.0001): With levels <5.0 µg/mL, 7% of patients were toxic; with levels of 5 to 10 µg/mL, 14%; with 10 to 15 µg/mL, 24%; with 15 to 20 µg/mL, 34%; and with >20 µg/mL, 59%. The correlation between levels and tolerability was independent of concurrent medication. Increasing efficacy, as measured by seizure freedom for a 6-month period, occurred up to levels of >20 µg/mL.

Conclusions: There is a correlation between LTG serum level and tolerability, independent of the use of other AEDs. Adverse effects requiring a dose change are uncommon with the most frequently encountered LTG concentrations (<10 µg/mL) and occur in only 7.4% of patients at levels obtained during the majority of clinical trials (<5 µg/mL). An initial target range of 1.5 to 10 µg/mL is suggested, though higher levels, up to >20 µg/mL, are often tolerated and can lead to additional efficacy in refractory patients.

Received December 5, 2003. Accepted in final form May 12, 2004.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the September 28 issue to find the title link for this article.

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