Effect of oral contraceptives on lamotrigine levels depends on comedication

Objectives To evaluate prospectively the influence of cyclic oral contraceptive (OC) use on lamotrigine (LTG) serum levels when used in combination therapy. Methods Women with epilepsy using LTG in combination with valproate (VPA; n = 7), carbamazepine (CBZ; n = 3) or oxcarbazepine (OXC; n = 1) were evaluated during two periods of 28 days cyclic OC use, monitoring antiepileptic drug (AED) levels every other day with the dried blood spot sampling method. Results were compared with women on LTG monotherapy and OCs (n = 12). Pharmacokinetic analysis was performed using NONMEM software. Results Mean study population value of LTG clearance estimated by the final model was 3.17 l/h. Introduction of covariates for comedication (VPA, CBZ, OXC and OC) significantly reduced the between‐subject variability. A significant influence of OC comedication on LTG clearance was seen in both LTG monotherapy (clearance with OC 4.02 ± 0.38 l/h, OC‐free week 3.03 ± 0.39 l/h) and in LTG‐CBZ combination (clearance with OC 4.95 ± 0.15 l/h, OC‐free week 4.15 ± 0.26 l/h). No influence of OC was found in LTG‐VPA combination (clearance with OC 0.99 ± 0.16 l/h, OC‐free week 0.90 ± 0.15 l/h). Conclusions Adding OCs to LTG monotherapy or the combination LTG‐CBZ significantly increased the LTG clearance and thus reduced LTG serum levels. In the combination LTG‐CBZ, OCs had a non‐significant effect on CBZ clearance. No significant influence of cyclic OC use on LTG or VPA clearance was found when these AEDs were used in combination.