Empiric dosing strategies to predict lamotrigine concentrations during pregnancy

Abstract

IntroductionMaintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy.ObjectiveOur objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity.MethodsLamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one‐compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single‐patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population‐level simulations (N = 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively.ResultsIndividual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6–8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%–100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%–100% of women).SignificanceA substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary “one‐size‐fits‐all” philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.

Step Climb Dosing Guidance From Simulation Studies on Lamotrigine Concentration Changes During Pregnancy

“…The current study by Barry et al 5 adds to previous simulation reported by Pa et al, 6 which evaluated a single scenario of LTG dose increase regimen (25, 50, and 25 mg per dose for each subsequent trimester) from a preconception dose of 150 mg twice daily (thus, 175 mg, 225 mg, and 250 mg twice daily) and assuming equal clearance rate changes for all simulated pregnancies, as sufficient dose increments to maintain the target LTG serum concentrations. 6 Barry and colleagues simulate, at individual and population levels, various LTG dose adjustment regimens (no-change, double-dose, 25 mg every 2 weeks, 25 mg every 4 weeks, 50 mg every 4 weeks, 100 mg every 4 weeks) to LTG-exposed pregnancies from the 2 known subpopulations of clearance (high and low change) starting from different preconception daily doses (100 mg, 200 mg, 300 mg, 400 mg).…”

“…Threshold for efficacy risk was set at 65% lower than preconception LTG serum concentrations and threshold for toxicity was set as twice the preconception concentrations. 5 All 24 dose adjustment scenarios predicted lower than 65% preconception concentration (and risk of seizures) at 3 to 26 weeks' gestation in the high change group, whereas this was observed only in the no-change regimen in the low change group, late in the pregnancy. With LTG dose unchanged in the high clearance change group, 65% lower than preconception LTG levels are expected as early as 6 to 8 weeks, with risk of seizures of 7% to 100% depending on preconception dose.…”

“…For this subpopulation, the regimen of 100 mg increase every 4 weeks showed the least risk of loss of efficacy. 5 For the low clearance change group, whereas the no-change regimen was considered the best regimen to avoid toxicity, this same regimen predicted a concentration below 65% by 33 weeks of pregnancy, thus potentially increasing risk of loss of efficacy in the third trimester. 5 Simulation studies overcome (with limitations) the lack of feasibility to perform clinical trials on pharmacokinetics of ASM dose changes in pregnant women and can provide useful insights to guide our management discussions with pregnant WWE on LTG.…”

“…5 For the low clearance change group, whereas the no-change regimen was considered the best regimen to avoid toxicity, this same regimen predicted a concentration below 65% by 33 weeks of pregnancy, thus potentially increasing risk of loss of efficacy in the third trimester. 5 Simulation studies overcome (with limitations) the lack of feasibility to perform clinical trials on pharmacokinetics of ASM dose changes in pregnant women and can provide useful insights to guide our management discussions with pregnant WWE on LTG. If serum concentration monitoring is available at preconception and during early pregnancy, high or low clearance change profiles can be suggested, and safer adjustment regimens can be adopted to maintain therapeutic concentrations and efficacy while avoiding toxicity.…”

“…Threshold for efficacy risk was set at 65% lower than preconception LTG serum concentrations and threshold for toxicity was set as twice the preconception concentrations. 5 …”