Graduate Research Assistant University of Minnesota Minneapolis, Minnesota
Rationale: Lamotrigine (LTG) is one of the most commonly prescribed antiseizure medications in women with epilepsy (WWE) during childbearing years. Due to probable upregulation of glucuronidation involved in LTG metabolism by estradiol, addition of combined oral contraceptives (COCs; progestin and ethinyl estradiol) to LTG therapy can decrease LTG concentrations. Little data exist describing the extent of enzyme induction or changes in LTG concentrations making it difficult for clinicians to estimate the LTG dose changes needed when COCs are added. Our objective was to characterize the changes in LTG concentrations from different dosing scenarios using data from a cohort of women of childbearing age who were treated with co-administered COCs. Methods: LTG apparent clearance (LTG CL) was determined from an observational study of WWE who were receiving LTG with or without COCs from a tertiary epilepsy clinic (Emory University, Atlanta, GA). Inclusion criteria were women 18-45 years prescribed COCs and LTG, stable LTG dose for > 4 weeks, for > 3 days, and no interacting co-medications. Additional pharmacokinetic parameters were identified from the literature.1 The pre-COC LTG baseline was designated the target concentration, and the ratio to target concentration (RTC) of < 0.65 was calculated as the threshold at which the risk of seizure worsening increases. LTG concentrations of > 15 ug/mL and > 2.0 RTC were used as thresholds at which LTG side effects were more likely.We simulated LTG concentrations when COCs are co-administered with LTG using a commonly prescribed 24 days of active pill and four days of placebo pill COC formulation. Five LTG dose change scenarios were simulated for 200 individuals each: 1) no change in dose, 2) 25% increase in LTG dose when COC is added, 3) 50% increase in LTG dose, 4) 100 mg flat increase in LTG dose and, 5) a 100 mg increase if pre-COC total daily dose is < 400 mg/day, or otherwise a 200 mg increase in LTG dose. For every simulation, we calculated the following comparison metrics between scenarios: percentage of the population with at least one incidence of 0.65 RTC; at least one incidence of > 15 ug/mL; and at least one incidence of >2.0 RTC. Results: LTG CL was 2.83 L/hr (N=25) for WWE on COC and 2.22 L/hr (N=31) for WWE not on COC (p = 0.005). Without a dose change the LTG trough concentrations decreased by approximately 40% as compared to baseline by the second week of COC administration (Figure 1). The 50% increase in dose scenario had less than 2% of the population below 0.65 RTC when compared to 10-30% for other scenarios. Although individuals belonging to the dose modification groups had concentrations > 15ug/mL ( >60% at 500 mg/day pre-COC), none had concentrations > 2.0 RTC. Conclusions: Our study presents the possible impact of different LTG dosing regimen modifications when LTG is co-prescribed with a COC. Simulations show that a 50% increase in LTG dose at the start of the COC performed the best, with maintenance of pre-COC LTG baseline levels while balancing possible toxicity concerns. Prospective studies are required to evaluate and validate these dosing scenarios.
References: 1. Hussein Z, Posner. Br J Clin Pharmacol. 1997;43(5):457-465 Funding: Please list any funding that was received in support of this abstract.: NIH P50 NS16308, University of Minnesota Doctoral Dissertation Fellowship 2019-2020 Click here to view image/table