Bidirectional interaction of valproate and lamotrigine in healthy subjects

• Published in: Clinical pharmacology and therapeutics Vol. 60; no. 2; p. 145
• Main Authors: Anderson, G D, Yau, M K, Gidal, B E, Harris, S J, Levy, R H, Lai, A A, Wolf, K B, Wargin, W A, Dren, A T
• Format: Journal Article
• Language: English
• Published: United States 01-08-1996
• Subjects: Analysis of Variance; Anticonvulsants - administration & dosage; Anticonvulsants - adverse effects; Anticonvulsants - pharmacokinetics; Anticonvulsants - pharmacology; Drug Administration Schedule; Drug Interactions; Half-Life; Humans; Male; Reference Values; Time Factors; Triazines - administration & dosage; Triazines - adverse effects; Triazines - pharmacokinetics; Triazines - pharmacology; Valproic Acid - administration & dosage; Valproic Acid - adverse effects; Valproic Acid - pharmacokinetics; Valproic Acid - pharmacology
• ISSN: 0009-9236
• DOI: 10.1016/S0009-9236(96)90130-7

To evaluate the steady-state pharmacokinetics of lamotrigine and valproate at three dosing levels of lamotrigine in normal volunteers receiving steady-state therapeutic doses of valproate.
This was an open-label, randomized, three-way crossover study of 18 normal male volunteers. Subjects received oral valproate (500 mg Depakote twice a day) throughout the study. Each subject subsequently received three oral dosage regimens of lamotrigine (50, 100, or 150 mg/day) for 1 week each, with a 2-week washout period between lamotrigine treatment periods. Valproate and lamotrigine trough plasma samples were determined by a capillary gas chromatography method and immunofluorometric assay, respectively. Urine samples were assayed for 11 valproate metabolites by gas chromatography/mass spectrometry.
When compared to other studies in which lamotrigine was administered with no concurrent antiepileptic drug, concomitant valproate markedly increased the half-life of lamotrigine and decreased lamotrigine clearance, without substantial alteration in the linear kinetics of the drug. The addition of lamotrigine was associated with a small but significant 25% decrease in steady-state valproate plasma concentration. Oral clearance of valproate was increased (from 7.2 +/- 1.1 ml/hr/kg before lamotrigine treatment to 9.0 +/- 2.0 ml/hr/kg on day 28; p < 0.05). The formation clearance of the hepatotoxic valproate metabolites, 2-n-propyl-4-pentenoic acid (4-ene-valproate) and 2-propyl-2,4-pentadienoic acid [2(E),4-diene-valproate], was unaffected by lamotrigine administration.
As a consequence of the interaction between lamotrigine and sodium valproate, a dosage reduction of lamotrigine should be considered in patients taking a combination of valproate and lamotrigine.