Abstracts

Rationale: It is known that lamotrigine (LTG) clearance (CL) can increase during pregnancy although approximately 25% of women experience little to no change in LTG CL during pregnancy (1). Due to unpredictability of clearance changes, and since women can experience increases in seizure frequency when levels fall to <65% of preconception baseline (2,3), therapeutic drug monitoring (TDM) is recommended. There is no guidance for dosing in the absence of availability of timely LTG blood levels. Some physicians report making one empiric adjustment during early pregnancy. Our objective was to simulate three dose adjustment options in pregnant women with epilepsy (PWWE) based on published pharmacokinetic data in women who do and do not experience a high increase in LTG CL. Methods: Data on volume of distribution, bioavailability and absorption rate constant for LTG were identified from the literature (3). LTG clearance changes were modeled to follow high clearance change (HCC) during pregnancy as previously reported (4). Clearance values were added to the model as a linear increase with respect to gestational week. A one-compartment model was used to describe the plasma concentration-time profile of LTG in pregnancy. The model was developed and simulated in the R package mrgsolve (Metrum Research Group). The time point where the concentrations fall to <65% of preconception (i.e., concentrations decrease by 35% or more) was determined. Three dosing scenarios were considered at this time point: no dose change from preconception dose, a single 25% dose increase, and a single 100% dose increase. A second simulation was performed for a low clearance change (LCC) group. Similar dose changes were added to the LCC at the same time point determined by the HCC group. Results: In the HCC group, concentrations fell to ‹65% preconception levels at gestational week 8. If a 25% dose increase was administered at week 8, levels were maintained above the ‹65% baseline cutoff until gestational week 16. Following a 100% dose increase, concentrations remained above the ‹65% baseline cutoff until gestational week 28. For the LCC group, simulated concentrations do not fall to ‹65% of baseline if the dose is not changed during pregnancy. When doses are increased by 25% or 100% at week 8 for the LLC group, resulting concentrations are predicted to be higher than baseline throughout pregnancy and could be in a clinically toxic range depending on the preconception level. Conclusions: A priori dose adjustments in the absence of TDM would be problematic for most women. For LCC women, our simulation indicates that dose increases could reach clinical toxicity depending on pre-conception levels. In contrast, for HCC women LTG concentrations would fall to ‹65% of their pre-pregnancy level at gestational week 8, and a dose increase would be needed to re-establish preconception levels. However, a single dose change would not be enough to maintain levels throughout pregnancy. The size of the dose increase determines when this occurs (after gestational week 16 for a 25% dose increase and after week 28 for a 100% dose increase). The group a woman belongs to (LCC or HCC) can drastically change the LTG levels during pregnancy. Further studies are needed to prospectively identify to which clearance group a woman belongs to determine if dose change(s) are needed without extensive therapeutic drug monitoring. Funding: Funded by the Epilepsy Foundation and the Patricia L Nangle Fund.