Abstract
Epilepsy is a common neurological disorder with clinically important gender differences in both the expression and the impact of epilepsy. Understanding the complex interactions between sex hormones, epilepsy and antiepileptic drugs (AEDs) can greatly improve the care for women with epilepsy. This thesis aims to further elucidate the relationship between
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sex hormones and AEDs, focusing on the influence of combined oral contraceptives (OCs) and hormonal changes in pregnancy as well as menopause on the pharmacokinetics of AEDs subject to extensive glucuronidation. Lamotrigine and monohydroxycarbazepine, the active metabolite of oxcarbazepine, are AEDs mainly cleared by glucuronide conjugation and widely used in women of reproductive age. Alteration in pharmacology and efficacy of these AEDs could have a significant clinical relevance by recurrence of seizures, increased seizure frequency, or increased frequency of adverse effects. This is even more important in pregnant women as uncontrolled seizures might affect both mother and child. During pregnancy, careful balancing is required in view of the dose-dependent risk of malformations with AED use.
This thesis starts with an overview of the literature on the complex interactions between hormones, particularly sex hormones, epilepsy and AEDs. In Chapter 2, we discuss the use of the blood spot method as well as population pharmacokinetic analysis in our studies. We continue in Chapter 3 with an exploration of lamotrigine kinetics within the menstrual cycle, after menopause, and with OCs. We established that regular menstrual cycles with apparently normal hormonal changes are not associated with an influence on lamotrigine clearance and therefore do not require adaptation of lamotrigine dosing. We confirmed previous findings that OCs increase lamotrigine clearance and further explored the time course of this change in lamotrigine levels. Our hypothesis that changing estrogen levels in menopause might have an effect on lamotrigine clearance seemed to be confirmed in this prospective study.
As lamotrigine is often used in combination with other AEDs we performed the prospective study described in Chapter 4 and concluded that the effect of OCs on lamotrigine levels depends on comedication. In Chapter 5 we retrospectively studied the relation between age, including perimenopausal age and pharmacokinetics of lamotrigine and monohydroxycarbazepine. For comparison we analysed data of carbamazepine clearance, as this AED is mainly metabolised by cytochrome P450 3A4. Age was a significant factor contributing to pharmacokinetic variability in patients on monotherapy lamotrigine, oxcarbazepine as well as on carbamazepine. We concluded that perimenopausal age does not seem to affect lamotrigine and monohydroxycarbazepine pharmacokinetics enough to warrant a change in individual dosing scheme.
Little is known about pregnancy-induced alterations in the pharmacokinetics of newer AEDs, especially when used in combinations. In Chapter 6 we showed pregnancy to be a strong inducer of the clearance of both lamotrigine and monohydroxycarbazepine when used in combination therapy. This stresses the importance of therapeutic drug monitoring of lamotrigine and monohydroxycarbazepine during pregnancy. Dosage adjustment of both drugs may be necessary to prevent breakthrough of seizures or increased seizure frequency.
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