Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects

Purpose: The antiepileptic drugs (AEDs) retigabine (RGB) and lamotrigine (LTG) undergo predominantly N-glucuronidation and renal excretion. This study was performed to evaluate potential pharmacokinetic interactions between both AEDs. Methods: Twenty-nine healthy male subjects participated in the study. Group A (n = 14) received single oral 200-mg RGB doses on day I and day 7, and 25 mg o.i.d. LTG on days 3-8. Group B (n = 15) received single oral 200-mg LTG doses on day I and day 17, and was up-titrated to 300 mg RGB b.i.d. on days 6-20. Blood samples were collected to compare the pharmacokinetics of both AEDs and the N-acetyl metabolite of RGB (AWD21-360) after single and concomitant treatments. Results: RGB was rapidly absorbed and eliminated with a mean half-life (t(1/2)) of 6.3 +/- 1.1 h and an apparent clearance (CL/F) of 0.69 +/- 1.4 1/h/kg. Under co-administration of LTG, mean RGB t(1/2) and area under the plasma concentration-time curve (AUC) were increased by 7.5% (P = 0.045) and 15% (P = 0.006), respectively, while CL/F was decreased by 13% (P = 0.06). Consistent results were obtained for AWD21-360. LTG was moderately rapidly absorbed, eliminated with a mean t(1/2) of 3 7 +/- 10.4 h and a CL/F of 0.028 +/- 0.007 1/h/kg. Under co-administration of RGB, mean LTG t(1/2) and AUC decreased by 15% and 18%, respectively, while CL/F increased by 22% (all parameters, P = 0.001). Conclusions: RGB and LTG exhibit a modest pharmacokinetic interaction on each other. The slight decline in RGB clearance due to LTG is believed to result from competition for renal elimination rather than competition for glucuronidation. The induction of LTG clearance due to retigabine was unexpected since RGB did not show enzyme induction in various other drug-drug interaction studies. Further studies in patients are needed to assess the clinical relevance of these findings for concomitant treatment with both drugs in the upper recommended dose range.