Influence of concomitant antiepileptic drugs on plasma lamotrigine concentration in adult Japanese epilepsy patients

Lamotrigine (LTG) is an antiepileptic drug (AED) that was approved in Japan in 2008. We evaluated the influence of AEDs that induce hepatic enzymes (including phenytoin (PHT), phenobarbital (PB), carbamazepine (CBZ)), valproic acid (VPA), and various combinations of these drugs, on plasma LTG concentration in adult Japanese epilepsy patients. A total of 621 patients (mean age 34.4±11.8 years) were evaluated retrospectively. We calculated the concentration to dose ratio (CD ratio) for LTG with different AED regimens, and employed multiple regression analysis to determine factors influencing the LTG concentration. There was a linear correlation between the dose and concentration of LTG in patients treated with LTG (group I), LTG+VPA (group II), LTG+inducers (group III), or LTG+VPA+inducers (group IV). The mean CD ratio of patients on LTG monotherapy was 1.43±0.4 (μg/mL)/(mg/kg). When LTG was combined with VPA, the CD ratio increased about 2.2-fold, but there was no significant correlation between the CD ratio and VPA concentration. The mean CD ratios calculated in patients receiving LTG+PHT, LTG+PB, and LTG+CBZ were 0.56, 0.84, and 0.91, respectively. Addition of PHT significantly reduced the CD ratio in a concentration-dependent manner, in comparison with PB and CBZ (p<0.005 and p<0.001, respectively). Stepwise multiple regression analysis showed that the coefficient of determination of groups I, II, III, and IV were 0.94, 0.94, 0.90, and 0.91, respectively. In the clinical setting, these findings can help to estimate LTG concentrations and predict the inducing or inhibiting effects of concomitant AEDs.