Paracetamol decreases steady-state exposure to lamotrigine by induction of glucuronidation in healthy subjects

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 4day 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 (100mg daily) over 36days, and blood and urine sampling was performed in a non-randomized order with and without paracetamol (1g 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 127moll(-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 2.8lh(-1), while the trough value of lamotrigine was reduced by 25% (95% CI 12%, 36%, P=0.003) from 5.3 to 3.9 moll(-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.