Lamotrigine Serum Concentrations under Valproate Comedication: “Contraindication” or “Safe Combination”?

Introduction

In our laboratory we analyse the concentrations of various psychopharmaceuticals from serum samples, which are sent to us from a broad spectrum of hospitals. Among a total number of 685 lamotrigine serum samples analysed in our laboratory between March 2005 and April 2007, 117 specimens (11.7% of all lamotrigine specimens) were identified that were obtained from patients under valproate comedication [10]. In Germany, both drugs are licensed for the treatment of epilepsy. Valproate has an additional indication for the treatment of acute mania as well as for prevention of bipolar disorders, while lamotrigine is the choice for the prevention of depressive episodes in bipolar disorders [1] [2] [3]. Lamotrigine is a phenyltriazine derivative and structurally different from all other antiepileptic drugs. The half-life of lamotrigine is reported to be 24.1±5.7 h under monotherapy [7]. Its biotransformation involves direct glucuronidation by UGT1A4 (uridine-glucuronyltransferase isoenzyme 1A4) to the pharmacologically inactive 2N-glucuronide, with the oxidative liver enzymes (the cytochrome P₄₅₀ system) not being involved [9]. Valproate is known to be a potent inhibitor of this metabolic pathway resulting in a three-fold increase of the lamotrigine elimination half-life, whereas valproate concentrations are not significantly changed under lamotrigine comedication [15] [16]. The combined use of the two drugs therefore results in significantly higher lamotrigine serum concentrations and the risk of severe side effects [8] [19]. Nevertheless, combination is possible and of certain benefit in bipolar disorders [20]. A tentative therapeutic reference range of 1-4 mg/L has been suggested for lamotrigine when used as antiepileptic drug to prevent grand mal seizures [6] [17]. There is so far no therapeutic reference range for its use in psychiatry for relapse prevention in bipolar disorders. Until better evidence is available, the therapeutic reference range for its use as an antiepileptic substance is been tentatively applied for the application of lamotrigine in bipolar disorders, too.

Based on published lamotrigine clearance data, our laboratory in Regensburg complementary adds a dose-related reference range to the therapeutic reference range to identify individual abnormalities in pharmacokinetics such as interactions with other drugs, food or stimulants, gene polymorphisms causing poor or rapid metabolism as well as alterations of drug elimination caused by chronic kidney or liver diseases. Information on compliance of the patient and on steady state conditions of the drug is also provided [12] [13] [14]].

Pharmacokinetic data, underlying the calculation of our dose-related reference ranges, are:

D_e/τ×F=c×Cl_t and c=D_e/(24 h×Cl_t) (for τ=24 h, F=100%)

D_e=maintenance dose [mg], F=bioavailability, τ=dosage interval [h], Cl_t=total clearance [mL/h], c=drug concentration [ng/mL].

In the case presented below, lamotrigine blood concentrations were determined by means of high performance liquid chromatography (HPLC) using the column-switching technology established in our laboratory for routine measurements [11].

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