Abstracts

Rationale: Lamotrigine ((LTG) has become an increasingly popular antiepileptic drug (AED) for the treatment of women with epilepsy of childbearing age. Studies have shown that LTG clearance progressively increases during pregnancy and swiftly returns to baseline after delivery (Hann et al, 2004; Pennell et al, 2004), changes that may lead to seizures during pregnancy and toxicity in the postpartum period in the absence of dose adjustments. Because of this, monthly LTG concentrations are obtained in these women. Ideally a non-invasive means of monitoring LTG concentrations could be used. The aim of this study was to determine the accuracy of salivary LTG monitoring in pregnancy. Methods: Pregnant women with epilepsy on stable doses of LTG for at least two weeks were invited to participate. Trough total LTG concentrations were obtained during each month of pregnancy and postpartum at 24, 48 and 72 hours, 1 week and 3 months. At the same time points, subjects chewed on a piece of paraffin for 5 minutes to produce a stimulated saliva sample. AEDs were adjusted over the course of pregnancy as clinically indicated. Time was categorized into baseline (antepartum), pregnancy trimesters, and a 3-month postpartum period. Apparent clearance (AC, mg/d/[mg/L]) using serum and salivary concentrations was calculated as daily dose(mg)/matrix concentration (mg/L). The generalized estimating equations method was used to compare AC according to serum and salivary concentrations across time periods, relative to baseline values. Linear mixed models were used to test the relationship between serum and salivary concentrations. The square root of LTG levels was employed for data normalization. Time and subject identification number were entered into the model as crossed random effects, while salivary concentration was considered a fixed effects predictor. Time and dose interaction effects were included in the final model if significance was attained. Results: During the study period, 105 concurrent serum and salivary concentrations were obtained from 11 women. Median total serum concentration was 5.1 mcg/mL (IQR 2.5 – 8.0), and median salivary concentration was 2.9 mcg/mL (IQR 1.1 – 5.3). Seventy-nine percent of subjects were on a twice-daily dosing schedule. According to serum levels AC increased by 209% during the 1st trimester, 173% during the 2nd trimester, 138% during the 3rd trimester, and 40% during the postpartum period. Salivary concentrations resulted in similar changes in AC across time periods. Despite these fluctuations in AC, mixed models indicated a stable relationship between serum and salivary concentrations during all time periods. The model coefficient was 0.89 (p<0.001) with Wald χ2(1) equal to 178.3 (p<0.001), without significant time or dose interaction effects. Conclusions: Salivary LTG concentrations correlate well with serum concentrations. Therefore this method may be a less invasive, clinically more desirable alternative of monitoring LTG concentrations during pregnancy and postpartum in women with epilepsy. Supported by a grant from GlaxoSmithKline