Abstracts

Rationale: Although it is known that lamotrigine (LTG) clearance (CL) changes during pregnancy and therapeutic drug monitoring (TDM) is recommended, there are no recommendations for LTG dose adjustments when timely LTG plasma concentration assays are not available. Studies have shown that LTG concentration decreases of ≥35% of preconception baseline are associated with an increased risk of seizures(1). Additionally, evidence exists for the presence of two subpopulations of women based on the change in drug clearance: high clearance change (HCC) group with increases of over 200% on average by the end of pregnancy and low clearance change (LCC) group with very little CL increases in pregnancy(2). Our objective was to determine LTG concentrations from various dosing adjustment regimens in pregnant women with epilepsy based on published pharmacokinetic data. Methods: We first identified information on LTG pharmacokinetic parameters from the literature(2,3). The pharmacokinetic information was used to create a one-compartment model for simulations. We performed population simulations for both HCC and LCC groups to observe the population behavior for various dosage regimens. Six dosing scenarios (no change in dose, dose doubling at gestational age 8 and 25, dose increase by 25 mg every 15 days, 25 mg every month, 50 mg every month, and 100 mg every month) at four different preconception doses (total daily doses of 100, 200, 300, and 400 mg) were simulated for 1000 individuals per simulation. For every simulation, we calculated metrics on both efficacy (less than 0.65 ratio to target concentration (RTC)) and safety (cutoff of 15 ug/ml) to compare between the various scenarios. Results: For the HCC group 100% of simulated individuals who have no change would have at least one concentration below 0,65 RTC (greater than 35% of preconception baseline), whereas for a dose change of 25 mg increases every 2 weeks or 50 mg every month showed less than 10% of the population would experience at least one concentration below. For the LCC group, 0% of individuals would have a concentration below the cutoff at any dosing regimen simulated; however, a greater proportion of the population would be above a level of 15 ug/ml indicating possible toxicity. A 25 mg increase every 2 weeks or 50 mg every month gave the best risk/benefit ratio in both HCC and LCC groups until gestational week 20. After 20 weeks, the HCC group fell below 35% of preconception baseline and LCC group tends to exceed toxic levels. Conclusions: These results show that a “one-size fits all” philosophy does not work for LTG dosing in pregnant women with epilepsy and reinforces the need for TDM. Although these simulations illustrate some dosage regimens to be beneficial, they will ultimately result in subtherapeutic levels in HCC or toxic levels in LCC for some patients. Further studies are needed to prospectively identify which clearance group a woman falls in order to determine if a dose change is needed without extensive TDM.References1. Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug monitoring, and seizure frequency. Neurology. 2008;70(22 Pt 2):2130-2136. doi:10.1212/01.wnl.0000289511.20864.2a2. Polepally AR, Pennell PB, Brundage RC, et al. Model-based lamotrigine clearance changes during pregnancy: Clinical implication. Ann Clin Transl Neurol. 2014;1(2):99-106. doi:10.1002/acn3.293. Hussein Z, Posner J. Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data. Br J Clin Pharmacol. 1997;43(5):457-465. http://www.ncbi.nlm.nih.gov/pubmed/9159559. Funding: No funding