Paracetamol decreases steady‐state exposure to lamotrigine by induction of glucuronidation in healthy subjects. (25th January 2016)

• Record Type: Journal Article
• Authors: Gastrup, Sandra; Stage, Tore Bjerregaard; Fruekilde, Palle Bach Nielsen; Damkier, Per
• Is Part Of: British journal of clinical pharmacology. Volume 81:Number 4(2016:Apr.)
• Page Start: 735
• Page End: 741
• Publication Date: 2016-01-25
• Subjects: drug‐related side effects -- epilepsy -- seizure -- uridine diphosphate glucuronosyltransferase; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12840
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aim: Patients 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. Methods: Twelve 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. Results: Co‐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 . Conclusion: Paracetamol 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.