Abstracts

Rationale: Although there is a relationship between lamotrigine (LTG) clearance and estradiol levels during pregnancy, how early the relationship begins and the rate of change are unknown. Our objective was to quantitate the relationship of LTG apparent clearance (CL/F) and estradiol concentrations during the first trimester in women with epilepsy who were 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), a sub-study of Women with Epilepsy: Pregnancy Outcomes and Deliveries (WEPOD). The study design involved frequent sampling prior to and early in pregnancy, a characteristic uncommon to studies of pregnancy which typically enroll women well after conception. Menstrual cycles were monitored, with a pregnancy test administered on day 35 if no menses occurred. Blood samples for measurement of LTG and estradiol concentrations were collected at baseline prior to pregnancy and at 5 time points within the first trimester (gestational weeks 5, 7, 9, 11, and 13). LTG concentrations were measured using a validated LC/MS assay (1) and estradiol concentrations were measured via LC/MS/MS at Brigham Research Assay Core. Subjects with a minimum of two LTG and estradiol level pairs were used. Preconception samples served as baseline levels. LTG CL/F was estimated via basic pharmacokinetic equations (daily dose divided by LTG concentration) with a non-linear mixed effects model (NONMEM, Icon).  Results: 151 observations representing 25 pregnancies (in 22 women) were included. The model performed well and had satisfactory goodness of fit plots with a CL/F estimate similar to a previous larger study (2). The population baseline LTG CL/F (preconception) was 2.22 L/hr (95% CI 1.91-2.55 L/hr) with a between subject variability of 27%. Population LTG CL/F increased by 0.863 L/hr for every 1 ng/ml increase in estradiol concentration during the first trimester and was variable between subjects at 79%.  Conclusions: LTG clearance and estradiol concentrations were highly correlated in the first trimester. These changes occurred early, before many women may know they are pregnant, and continued to increase through week 13. In most women, the increase in LTG CL paralleled the increase in estradiol concentrations. Although there was a relationship between estradiol and LTG clearance in individual women, they were not of the same magnitude in all subjects.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. Polepally AR, Pennell PB, Brundage RC., ZN Stowe, DJ Newport, AC Viguera, JC Ritchie, AK Birnbaum, Model-based lamotrigine clearance changes during pregnancy: Clinical Implication. Ann Clin Transl Neurol. 2014 Feb;1(2):99-106. Funding: Funded by the Epilepsy Foundation and the Patricia L Nangle Fund and the Milken Foundation