1. ¹Clinical Pharmacology Unit, University of Cambridge, Cambridge, UK
2. ²Department of Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Harlow, UK
3. ³Department of Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Research Triangle Park, NC, USA

Correspondence: Dr JGW Theis, Clinical Pharmacology Unit, University of Cambridge, Addenbrookes Centre for Clinical Investigation, Addenbrookes Hospital, Hills Road, Cambridge CB2 2GG, UK. Tel: +44 7830 073904; Fax: +44 7830 610802; E-mail: Jochen_Theis@hotmail.com

Received 31 January 2005; Revised 29 April 2005; Accepted 10 June 2005; Published online 27 July 2005.

Abstract

Epilepsy and bipolar disorder are commonly treated by combination drug therapy, such as lamotrigine and oxcarbazepine. To ensure the safety of this combination, information on pharmacokinetics and tolerability must be available. The objective of study was to evaluate the pharmacokinetics and tolerability of coadministered lamotrigine and oxcarbazepine in healthy subjects. This randomized, single-blind, parallel-group study comprised three cohorts: lamotrigine (200 mg daily) plus oxcarbazepine (600 mg twice daily), lamotrigine (200 mg daily) plus placebo, and oxcarbazepine (600 mg twice daily) plus placebo. Serial blood samples were collected at steady state to determine serum concentrations of lamotrigine and plasma concentrations of oxcarbazepine and its active metabolite 10-monohydroxy metabolite (MHD). Pharmacokinetic parameters were determined by noncompartmental methods. Tolerability was monitored through adverse event reports, clinical laboratory results, vital signs, and electrocardiograms. A total of 47 male volunteers received study drugs. At steady state, lamotrigine AUC_(0–24) and C_max were not significantly affected by oxcarbazepine cotherapy, nor were MHD AUC_(0–12) and C_max significantly affected by lamotrigine cotherapy. The most common adverse events, headache, dizziness, nausea, and somnolence, occurred more frequently during lamotrigine and oxcarbazepine combination therapy than during the monotherapy. No significant changes in clinical laboratory parameters, vital signs, or electrocardiograms were reported. In conclusion, the combination of lamotrigine and oxcarbazepine does not require dose adjustments based on pharmacokinetic data. However, it is important to recognize that the combination therapy was associated with more frequent adverse events.