Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy

Abstract

Objective: To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.

Methods: Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1-3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.

Results: AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05).

Conclusion: AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

Figure 1. Flow diagram for women enrolled in the study and subset used for clearance analysis or therapeutic drug monitoring (TDM)/seizure analysis

LEV = levetiracetam; WWE = women with epilepsy. Flow charts for other medications included in the study data available from Dryad (figure e-1) (doi.org/10.5061/dryad.91f0r82).

Figure 2. Mean relative levetiracetam clearance (95% confidence interval [CI]) by stage of pregnancy

Line chart depicts clearances as reflected by all values available (combined research laboratory and clinical laboratory values). Significant differences, marked by a star on the graph, are seen for each trimester (TM) when compared to the baseline (p < 0.05). Error bars represent 95% CI.

Figure 3. Mean antiepileptic drug relative clearance by stage of pregnancy

Line chart depicts clearances for oxcarbazepine (OXC) (orange line) and topiramate (TPM) (purple line) values. Significant differences, marked by a star on the graph, are seen for the 2nd and 3rd trimester clearance values when compared to the baseline relative values (p < 0.05). CI = confidence interval; PHT = phenytoin; TM = trimester; VPA = valproic acid.

Figure 4. Ratio to target concentration (RTC) in seizure worsening vs stable or improved seizure groups

Dashed horizontal line was placed at an RTC of 0.65, previously determined to be a threshold for seizure worsening. TM = trimester.