Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy

Objective: Lamotrigine (LTG) is approved for monotherapy following withdrawal from enzyme-inducing antiepileptic drugs. LTG is also frequently used in combination with sodium valproate (VPA), and withdrawal to monotherapy in this setting is also frequently desirable. Given the known pharmacokinetic interaction between these two drugs, clinically relevant questions that should be answered include (1) at what dose and/or concentration of VPA does this interaction begin, and (2) at what dose of VPA does maximal inhibition occur. Methods: LTG pharmacokinetics was evaluated using single-dose LTG (25 mg) given before and following low-dose VPA co-medication (125, 250, 375, 500 mg per day VPA) in healthy subjects. Serial blood samples were obtained over 120h post-dose in order to calculate LTG kinetic parameters including area under the concentration-time curve, apparent oral clearance, elimination half-life and percent inhibition of LTG clearance at each dosage level of VPA. Pharmacodynamic modeling was used to calculate EC50 values for this interaction. Results: LTG pharmacokinetic parameters were evaluated in adult healthy female & male volunteers. Mean trough VPA concentrations at doses of 125, 250, 375 and 500 mg per day were 6.5, 13.9, 16.1 and 31.9 μg/ml, respectively. Maximal theoretical inhibition of LTG oral clearance by VPA is approximately 65%, with an EC50 concentration value of approximately 5.6 μg/ml of VPA. Mean inhibition of LTG oral clearance during concomitant treatment with VPA 125, 250, 375 and 500mg per day was 30.8, 51.5, 52.8 and 50.3%, respectively. Conclusions: These data suggest that VPA inhibition of LTG clearance begins at very low VPA doses and concentrations. Importantly, maximal inhibition can be expected at VPA doses of approximately 500 mg per day, with the magnitude of inhibition diminishing at doses below this. These data provide useful information to develop a dosing algorithm to facilitate conversion to LTG monotherapy.