• Sandra Gastrup, Tore Bjerregaard Stage, Palle Bach Nielsen Fruekilde, and Per Damkier.
• Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense.
• Br J Clin Pharmacol. 2016 Apr 1; 81 (4): 735-41.

AimPatients receiving lamotrigine therapy frequently use paracetamol concomitantly. While one study suggests a possible, clinically relevant drug-drug interaction, practical recommendations of the concomitant use are inconsistent. We performed a systematic pharmacokinetic study in healthy volunteers to quantify the effect of 4 day treatment with paracetamol on the metabolism of steady-state lamotrigine.MethodsTwelve healthy, male volunteers participated in an open label, sequential interaction study. Lamotrigine was titrated to steady-state (100 mg daily) over 36 days, and blood and urine sampling was performed in a non-randomized order with and without paracetamol (1 g four times daily). The primary endpoint was change in steady-state area under the plasma concentration-time curve of lamotrigine. Secondary endpoints were changes in total apparent oral clearance, renal clearance, trough concentration of lamotrigine and formation clearance of lamotrigine glucuronide conjugates.ResultsCo-administration of lamotrigine and paracetamol decreased the steady-state area under the plasma concentration-time curve of lamotrigine by 20% (95% CI 10%, 25%; P < 0.001) from 166 to 127 μmol l(-1) . Concomitant administration of paracetamol increased the formation clearance of lamotrigine glucuronide conjugates by 45% (95% CI 18%, 79%, P = 0.005) from 1.7 to 2.8 l h(-1) , while the trough value of lamotrigine was reduced by 25% (95% CI 12%, 36%, P = 0.003) from 5.3 to 3.9 μmol l(-1) .ConclusionParacetamol statistically significantly induced steady-state lamotrigine glucuronidation, resulting in a 20% decrease in total systemic exposure and a 25% decrease in trough value of lamotrigine. This interaction may be of clinical relevance in some patients.© 2015 The British Pharmacological Society.

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