Effect of oral contraceptives on lamotrigine levels depends on comedication Wegner I, Wilhelm AJ, Lambrechts DAJE, Sander JW, Lindhout D. Effect of oral contraceptives on lamotrigine levels depends on comedication. Acta Neurol Scand: DOI: 10.1111/ane.12197. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. 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 Æ 0.38 l/h, OC-free week 3.03 Æ 0.39 l/h) and in LTG-CBZ combination (clearance with OC 4.95 Æ 0.15 l/h, OC-free week 4.15 Æ 0.26 l/h). No influence of OC was found in LTG-VPA combination (clearance with OC 0.99 Æ 0.16 l/h, OC-free week 0.90 Æ 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. I. Wegner 1,2 , A. J. Wilhelm 3 , D. A. J. E. Lambrechts 4 , J. W. Sander 1,5 , D. Lindhout 1,2 1 SEIN – Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands; 2 Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands; 3 Department of Clinical Pharmacology and Pharmacy, VU Medical Centre, Amsterdam, The Netherlands; 4 Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands; 5 UCL Institute of Neurology, NIHR University College London Hospitals Biomedical Research Centre, London, UK Key words: combination therapy; dried blood spot; epilepsy; lamotrigine; oral contraceptives; pharmacokinetics; serum concentration I. Wegner, SEIN – Epilepsy Institute in the Netherlands, Dr Denekampweg 20, 8025 BV, Zwolle, The Netherlands Tel.: +31 38 8457193 Fax: +31 38 8457170 e-mail: iwegner@sein.nl Accepted for publication September 30, 2013 Introduction Oestrogen-containing oral contraceptives (OCs) may reduce the serum concentration and efficacy of certain antiepileptic drugs (AEDs) by induc- tion of the uridine diphosphate glucuronosyl- transferase (UGT) system. Lamotrigine (LTG) is an AED widely used in the treatment of women with epilepsy of reproductive age. It is mainly cleared by glucuronidation and was the first AED to be evaluated in combination with OCs. Decreases of over 50% in serum LTG in women taking LTG and OCs concomitantly have been reported (1–3). Changes in serum levels of LTG may have significant clinical relevance with, for example recurrence of seizures, increased seizure frequency or increased frequency of adverse events. LTG is often used in combination with other AEDs, and it is of interest to know what effect OCs will have on LTG levels in women with epilepsy using LTG in combination therapy. We evaluated the influence of cyclic OC use on serum LTG levels in women with epilepsy on the frequently used combinations LTG-valproate (VPA), LTG-carbamazepine (CBZ) or LTG- oxcarbazepine (OXC) in comparison with the effect of OCs on LTG monotherapy. We also investigated the effect of cyclic OC use on serum levels of VPA and CBZ when used in combina- tion with LTG. We aimed to evaluate also a pos- 1 Acta Neurol Scand DOI: 10.1111/ane.12197 © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA