Time course of reversal of valproate-mediated inhibition of lamotrigine

PURPOSE Conversion to lamotrigine (LTG) monotherapy from sodium valproate (VPA) is complicated by the robust pharmacokinetic interaction between the two AEDs. This study examined changes in LTG serum concentrations immediately following VPA discontinuation. METHODS Ten healthy female and male adult subjects were initiated on LTG (Lamictal) 10 mg orally every morning for 30 days and VPA (Depakote ER) 500 mg orally every morning for 14 days. Morning trough (pre-dose) venous blood samples were obtained for determination of LTG and VPA concentrations on study days 14, 15, 16, 18, 20, 22, 24, 26, 28, and 30. Following the collection of the blood sample on day 15, VPA was discontinued. RESULTS Despite stable LTG dosage serum concentrations on study day 20, 22, 24, 26, and 28, all were significantly lower compared to baseline (p < 0.05). CONCLUSIONS These observations demonstrate that the pharmacokinetic interaction between LTG and VPA is reversible, and that de-inhibition appears to follow a predictable time course. Complete offset, or reversal of this interaction takes place 10-14 days after VPA discontinuation. Our data also confirms the observation that LTG oral clearance may be inhibited by very low concentrations of VPA. These data support the conversion algorithm suggested by the manufacturer, and provide guidance to the clinician. These data provide clinically useful information in developing a dosing algorithm for converting patients to LTG monotherapy.