Individual changes in lamotrigine plasma concentrations during pregnancy
Introduction
Women suffering from epilepsy poise a special therapeutic challenge during pregnancy. It has been established that about 15–37% of the patients experience an increase in seizure frequency during pregnancy (Pennell, 2003). A major cause explaining this increase in frequency is the increased elimination of anti-epileptic drugs (AED) both due to increased renal elimination as well as altered hepatic enzyme activity (Pennell, 2003). In addition, non-compliance has also been suggested (Williams et al., 2002).
A recent study found a 75% increase in seizure frequency in patients on lamotrigine (LTG) treatment during pregnancy (De Haan et al., 2004). It was concluded that the deterioration was associated with a 40% decrease in the ratio of plasma LTG concentration-to-dose compared to baseline, the decrease occurring primarily between the 20th and 30th gestational week. The main reason for the drop in the ratio seems to be increased renal clearance (Tran et al., 2002, Pennel et al., 2004).
In Denmark pregnant women suffering from epilepsy are in general offered treatment control in specialized units dedicated to treating epilepsy. In this study a consecutive series of pregnant patients on LTG monotherapy is reported. As standard for all patients the dose of LTG is adjusted to maintain a fairly stable concentration of LTG in plasma. The aim of the present study was to evaluate treatment efficacy in terms of seizure control as well as evaluating whether deterioration was related to changes in the ratio of LTG plasma level-to-dose.
Section snippets
Methods
The 11 consecutive pregnant patients suffering epilepsy treated in the period 1999–2003 at either the Danish Epilepsy Hospital in Dianalund (n = 6) or at the Epilepsy Clinic at Glostrup University Hospital (n = 5) were retrospectively studied. The diagnostic distribution is displayed in Table 1. All patients were on LTG monotherapy and their mean age was 26.5 years (range 22–30 years).
Recording of seizures was done through patients keeping a diary registering date of seizure as well as type of
Results
LTG mean daily dosage before pregnancy was 286 mg/day (range 75–750 mg/day). Due to decreasing LTG plasma concentrations during pregnancy, LTG dosages were averagely increased two times reaching a mean of 570 mg/day (range 200–1100 mg/day) in the third trimester (TM3). The major decrease of LTG plasma levels was found during TM2. Compared with the pre-pregnancy value, the ratio of plasma concentration-to dosage decreased by 26.5% during TM1 (p = 0.1412), 65.1% during TM2 (p = 0.0058) and by 65.8%
Discussion
The data obtained in the present study is consistent with earlier findings (De Haan et al., 2004), both in terms of the need for an increased LTG dosage during pregnancy and in terms of seizure aggravation. The source of inter-patient variation in the ratio of LTG plasma concentration-to-dose is probably to be found in the hepatic elimination pathway of LTG. It is known, that about 70–90% of LTG is hepatically metabolised by UGT1A4, an isozyme of uridine diphosphate glucuronosyltransferase
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