Topiramate and lamotrigine pharmacokinetics during repetitive monotherapy and combination therapy in epilepsy patients

Purpose: To determine at steady state (in the same group of patients): (a) the pharmacokinetics (PK) of lamotrigine (LTG) with LTG monotherapy, (b) the PK of LTG concomitantly administered with topiramate (TPM) at three escalating TPM doses (100, 200, and 400 mg/day), (c) the PK of TPM at three escalating TPM doses while receiving fixed-dose LTG therapy, and (d) the PK of TPM with TPM monotherapy. Methods: This was an open-label, sequential, single-group, dose-escalating PK study in which 13 patients with epilepsy not optimally controlled with LTG received stable-dose LTG monotherapy for 2 weeks, followed by stable-dose LTG therapy combined with escalating doses of TPM for less than or equal to 16 weeks, stable-dose TPM therapy combined with tapered-dose LTG therapy for 4 weeks, and stable-dose TPM monotherapy for 2 weeks. Serial blood and urine samples were collected before and during TPM dosing, and safety data were collected throughout the study. Results: The exposure, or area under the plasma LTG concentration-time curve within a dosing interval at steady state (AUC(ss)), did not change in the presence of TPM, with mean AUC(ss) values ranging at each TPM dose level between 66 and 81 mg x h/L with concomitant LTG/TPM therapy compared with 77 mg x h/L with LTG monotherapy. No significant change was found in the steady-state peak (C-max) and trough (C-min) plasma levels of LTG in the presence and absence of TPM. The mean (+/-SD) oral clearance (CL/F) of TPM (400 mg/day) was 2.6 +/- 1.1 L/h when given alone and 2.7 +/- 0.7 L/h when given with LTG. The similarity of CL/F values also was reflected by the similar exposure (AUC(ss)), C-max, and C-min values of TPM in the absence, and presence of LTG. Conclusions: The results of this study show that no PK interaction-between TPM and LTG was observed at the doses used in this study.