Quantitative Pharmacological Approaches for Characterizing Lamotrigine Pharmacokinetics in Special Populations of Pregnancy, Postpartum and Breastfeeding Infants to Prospectively Optimize Dosing

Abstract

Lamotrigine (LTG) is one of the most prescribed antiseizure medications (ASMs) in women with epilepsy during pregnancy and postpartum. Pregnancy-related physiological changes are expected to alter LTG pharmacokinetics (PK) especially increases in apparent clearance (CL/F), leading to subtherapeutic concentrations and in-turn potential loss of efficacy and/or safety. This necessitates increases in LTG dose during pregnancy to maintain therapeutic LTG concentrations followed by a postpartum reduction in dose to prevent toxicity. In addition, infants born to mothers on LTG therapy are exposed to LTG via breastmilk, necessitating quantitative characterization of rate and extent of LTG exposure in infants and possible relationships with infant neurocognitive and developmental outcomes. Management of LTG therapy in pregnancy and postpartum is thus balancing seizures in mother while minimizing LTG exposure to fetus and infants. These special populations are understudied especially with respect to PK-pharmacodynamic (PK-PD) relationships. This dissertation work aims at characterizing changes to LTG PK in pregnancy, postpartum and in breastfeeding infants. In addition, this thesis explores feasibility of potential LTG dosing algorithms which maximizes exposure and safety during pregnancy. The long-term goal of this research work is to create robust evidence-based guidelines for dosing LTG in both pregnant women with epilepsy and their breastfeeding children.Investigations into CL/F changes in early pregnancy were performed in women with epilepsy maintained on LTG monotherapy who were planning to become pregnant. CL/F increased at the rate of 0.115 L/h for every gestational week with increases in CL/F observed as early as 5 weeks gestational age, often before women themselves know they are pregnant, and continue to increase through gestational week 13. The average increase in clearance by week 13 was approximately 1.6 times the preconception CL/F. Such rapid increases in LTG-CL would necessitate dose-adjustments relatively early in pregnancy. It was also identified that LTG-CL increased by 0.844 L/h for every 1 ng/ml of estradiol however gestational age was a more robust predictor of LTG-CL changes. This may potentially be due to gestational age reflecting additional factors, although neither was robust enough for clinical use owing to significant interpatient variability. We also identified a subpopulation of women who may not experience significance CL/F changes in early gestation however quantification of this group was limited by the small sample size. Our findings highlight the importance of planning and early detection of pregnancy and use of therapeutic drug monitoring (TDM) in this population. LTG CL/F changes in pregnancy and postpartum necessitate dose changes. However, there exists no consensus on dosing recommendations for these populations. Simulation based methods were used to understand the outcomes of LTG dosing changes and different regimens in pregnant women with epilepsy (PWWE) based on published data. We identified that without any dose changes women in the high CL/F change group could experience loss of efficacy as early as 8 weeks gestational age. At least two dose increases during pregnancy would be needed to prevent loss of efficacy. However, using the same two dose increase strategy in women with low CL/F change during gestation could possibly lead to toxic/unsafe LTG concentrations. These results show that a “one size fits all” philosophy does not work well for LTG dosing in PWWE based on current knowledge and reinforces the need for TDM. LTG CL/F was characterized in the largest cohort of PWWE and nonpregnant women with epilepsy (NPWWE) enrolled in the MONEAD study. During pregnancy, we identified two subpopulations of women that exhibited different rates of increase in LTG CL/F. The gestational age associated increase in CL/F displayed a 1.75-fold increase in pregnancy at the end gestation in a majority of the PWWE (91%) compared to no identifiable change in LTG CL/F in the remaining 9% closely reproducing a previous study performed in a smaller population. Clinical covariates available in the study failed to explain the difference in subpopulations. We anticipate genotypic variations in the activity or induction of UGT1A4 or polymorphisms in estrogen receptors could partly explain the varying degrees of enhanced CL/F between the two groups of pregnant women and may warrant further investigation. In the postpartum period, LTG CL/F reached baseline values by 3 weeks after birth necessitating dose tapering early in postpartum. After 3 weeks, the CL/F in postpartum PWWE was indistinguishable from NPWWE CL/F confirming that pregnancy related changes do not carry over to postpartum. Infant LTG exposure via breastmilk was quantified in breastfeeding infants exposed to LTG enrolled in the MONEAD study. Median infant LTG concentrations were approximately 28.9% of maternal concentrations with a range of 0.6-90.3% indicating significant infant exposure but also wide between infant variability pointing out the need to accurately characterize infant LTG PK. A physiology-based PK model (PBPK) methodology was utilized to incorporate mechanistic information of LTG disposition in both postpartum mother and infants to characterize LTG exposure with both models having predictions within 1.6-fold of observed levels. These models provide mechanistic understanding of LTG-CL changes in infants and predictions of infant exposures which can be used for exploring exposure-neurocognitive developmental relationships. This PBPK model serves as a framework for understanding PK and quantifying exposure of other commonly used drugs in these special populations and is not limited to the epilepsy therapeutic area. Overall, the studies presented in this thesis characterized the LTG PK in special underrepresented populations of women with epilepsy and their infants including pregnancy and postpartum and breastfed infants. The results of this thesis add robust evidence to inform clinical management of LTG therapy in PWWE.