The influence of oral contraceptives on lamotrigine clearance in patients on lamotrigine in combination with valproic acid, carbamazepine or oxcarbazepine as compared to patients on lamotrigine only.

Lamotrigine (LTG) is an anticonvulsant drug that is widely used in the
treatment of epilepsy in all age groups. A pharmacokinetic interaction between
LTG and combined oral contraceptives (OCs) was demonstrated in two small
retrospective studies(1,2), in a double-blind placebo controlled trial(3) and
in our previous study(4). In these studies, the use of OCs resulted in a 50%
reduction of the plasma level of LTG. Changes in plasma levels of LTG could
have a significant clinical relevance either by recurrence of seizures,
increased seizure frequency or by an increased frequency of adverse effects.
The changes in LTG clearance during OC use are probably due to steroid
induction of hepatic 2-N-glucuronidation, which is the major route of
metabolism for LTG. The pathway of glucuronidation is inhibited by the
anticonvulsant drug valproic acid (VPA) and is induced by enzyme inducing drugs
(e.g. rifampicine and enzyme inducing anticonvulsants)(5). OCs are also able to
induce glucuronide conjugating enzymes(6).
References
1. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels
reduced by oral contraceptives. Epilepsy Res 2001;47:151-154.
2. Sabers A, Öhman I, Christensen J, Tomson T. Oral contraceptives reduce
lamotrigine plasma levels. Neurology 2003;61:570-571.
3. Christensen J, Petrenaite V, Atterman J, et al. Oral contraceptives induce
lamotrigine metabolism: evidence from a double-blind, placebo-controlled trial.
Epilepsia 2007;48(3):484-489.
4. Wegner I, Edelbroek PM, Bulk S, Lindhout D. Lamotrigine kinetics within the
menstrual cycle, postmenopausal and with oral contraceptives. Neurology in
press.
5. Dickins M, Chen C. Lamotrigine. Chemistry, biotransformation, and
pharmacokinetics. In: Levy RH, Mattson RH, Meldrum BS, Perucca E, editors.
Antiepileptic drugs, 5th ed. Lippincott Williams and Wilkins;2002:370-379.
6. Shenfield GM, Griffin JM. Clinical pharmacokinetics of contraceptive
steroids. An update. Clin Pharmacokinet 1991; 20 (1):15-37.

In a previous prospective study(4), we investigated in detail the effect of OCs
on LTG clearance. However, LTG is frequently used in combination therapy. This
raises the question as to what extent and how co-medication with other
anti-epileptic drugs like VPA may alter the pharmacokinetic interaction between
LTG and OC. In this new prospective study we aim to analyse the effects of
frequently used comedication (VPA, carbamazepine (CBZ) and oxcarbazepine (OCB))
on the interference of OC hormones on LTG metabolism.

In an open, prospective study we will select women in the age of 18-40 years
that use OC in a stable dose as well as a stable dose of 1)LTG and VPA, 2)LTG
and CBZ, 3)LTG and OCB. In each woman we will study two consecutive cycles
starting with the first pill of a strip of OCs. Every other day serum levels of
the AEDs will be assessed, using a dried bloodspot method. At home, women will
obtain a finger puncture blood drop using an automatic disposable lancet, which
is then applied to a standardized filter paper. Samples will be sent to our
laboratory where they will be analysed.

There is no intervention.
There is no risk for the patient participating in this study.
The burden for the patient will be to obtain at home a finger puncture blood
drop every other day during a period of 8 weeks, using an automatic disposable
lancet.