Model‐based lamotrigine clearance changes during pregnancy: clinical implication

Abstract

Objective The objective of the study was to characterize changes in the oral clearance (CL/F) of lamotrigine (LTG) over the course of pregnancy and the postpartum period through a model-based approach incorporating clinical characteristics that may influence CL/F, in support of developing clinical management guidelines. Methods Women receiving LTG therapy who were pregnant or planning pregnancy were enrolled. Maternal blood samples were collected at each visit. A pharmacokinetic analysis was performed using a population-based, nonlinear, mixed-effects model. Results A total of 600 LTG concentrations from 60 women (64 pregnancies) were included. The baseline LTG CL/F was 2.16 L/h with a between-subject variability of 40.6%. The influence of pregnancy on CL/F was described by gestational week. Two subpopulations of women emerged based on the rate of increase of LTG CL/F during pregnancy. The gestational age-associated increase in CL/F displayed a ten-fold higher rate in 77% of the women (0.118 L/h/week) compared to 23% (0.0115 L/h/week). The between-subject variability in these slopes was 43.0%. The increased CL/F at delivery declined to baseline values with a half-life of 0.55 weeks. Interpretation The majority of women had a substantial increase in CL/F from 2.16 to 6.88 L/h by the end of pregnancy, whereas 23% of women had a minimal increase. An increase in CL/F may correspond to decreases in LTG blood concentrations necessitating the need for more frequent dosage adjustments and closer monitoring in some pregnant women with epilepsy. Postpartum doses should be tapered to preconception dose ranges within 3 weeks of delivery.

Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age

“…In relation to gestational week, the estimated baseline (prepregnancy) of LTG‐CL/F was 2.19L/hr, with an estimated increase in LTG‐CL/F of 0.115L/hr per gestational week. These estimates agree with a similar model from a separate larger number of women . The variability in our study was similar to the previous larger study before application of the mixture model.…”

“…Although small, this study contains some of the only LTG concentration data available during early pregnancy in women with epilepsy. In addition, we confirmed that this group of women is representative of pregnant women with epilepsy in general by comparing estimated clearance to a separate larger set of pregnant women with epilepsy . All concentrations were measured in the same laboratory and all measurements from each participant were run on the same assay to decrease interassay variability and increase the relevance of intrapatient variability.…”

Characterization of lamotrigine disposition changes during and after pregnancy in women with epilepsy

“…The changes characterized in the population model were consistent with the observed dose‐normalized‐concentration changes throughout gestation and increases in lamotrigine clearance in other studies 7,20,21,35 . The existence of two populations of pregnant women who exhibit differences in clearance is confirmatory to a smaller, independent study in 60 women 21 .…”

Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy

“…But this trend was not observed for total LTG clearance (Pennell et al, ). In this study, the extent of change in clearance was in the middle of the range compared with previous studies (Fotopoulou et al, ; Milosheska et al, ; Pennell et al, , ; Polepally et al, ; Reisinger et al, ). In a larger US‐based cohort study, the majority (77%) of women had a substantial increase in the oral clearance by the end of pregnancy, whereas 23% of women had a minimal increase (Polepally et al, ).…”