Abstracts

Rationale: In pregnant women with epilepsy therapeutic monitoring is frequently employed with the goal of maintaining drug concentrations similar to those found pre-pregnancy. Anticipating dose changes can be especially difficult with medications such as lamotrigine (LTG) that have changing pharmacokinetics throughout pregnancy. Although it is known that LTG clearance changes during pregnancy, most of these results are based on limited drug exposure data and detailed information is not available throughout the first trimester. Our objective was to describe changes in LTG apparent clearance (CL/F) during the first trimester in women with epilepsy who are taking LTG as monotherapy. Methods: Women receiving LTG monotherapy for seizure control, ages 18-40, who were planning to become pregnant were enrolled in the three-center observational, prospective cohort study, Pharmacogenomics-Pharmacokinetics of women with Epilepsy during Pregnancy (P-PEP), which is a sub-study of Women with Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD). The study design allowed frequent sampling early in pregnancy, a characteristic uncommon to studies of pregnancy which typically enroll women after becoming pregnant. Menstrual cycles were monitored, with a pregnancy test administered on day 35 if no menses occurred. Blood samples for measurement of LTG concentrations were scheduled to be collected at baseline prior to pregnancy and at 5 time points within the first trimester, at approximate gestational weeks 5, 7, 9, 11, and 13. LTG concentrations were measured using a validated LC/MS assay (1). Average change in apparent clearance (daily dose/concentration) per gestational week was estimated for all complete cases using generalized estimating equations, implemented with the "gee" package in R (2). Changes in CL/F included data from women with at least 2 concentrations and was calculated as latest concentration minus baseline concentration (defined as preconception or earliest available concentration). Results: 22 women representing 24 pregnancies were enrolled into the study. Mean and median baseline LTG clearances were 2.81 and 2.38 L/hour respectively (range 1.57 ?" 6.27). LTG clearance was affected by gestational week, and increased on average by 0.19 L/hour per gestational week (robust SE=0.05, p < 0.00005). Changes in clearance were observed as early as gestational week five. By the end of week 13, the estimated increase was 2.48 L/hr (104.2% increase from median baseline), corresponding to an approximate doubling from baseline. The median time to dose change occurred at nine weeks. Of the 20 women with at least two concentrations available, clearance was increased from baseline at the end of the first trimester in 15 individuals (75%). Conclusions: These results show that the increase in LTG clearance can begin early in the first trimester (often before women may know they are pregnant) and continue to increase through week 13. These findings highlight the importance of planning and early detection of pregnancy and therapeutic drug monitoring in this population. Future analysis will address how clearance continues to change beyond the first trimester. References: 1. Subramanian, M.; Birnbaum, A.K.; Remmel, R.P. High-speed simultaneous determination of nine antiepileptic drugs using liquid chromatography-mass spectrometry. Ther. Drug Monit. 2008, 30, 347?"356. 2. Vincent J Carey. Ported to R by Thomas Lumley and Brian Ripley. (2015). gee: Generalized Estimation Equation Solver. R package version 4.13-19. https://CRAN.R-project.org/package=gee Funding: Funded by the Epilepsy Foundation and the Patricia L Nangle Fund and the Milken Foundation