Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy

Abstract

Objectives To evaluate the pharmacokinetic changes in lamotrigine (LTG) from prepregnancy to postpartum and to assess the impact of therapeutic drug monitoring (TDM) on seizure management during pregnancy in a Chinese population. Methods A series of women who were on LTG monotherapy before conception or during pregnancy were included in this retrospective study. The clinical characteristics of the mothers and fetuses were collected. The apparent clearance (AC) and the ratio to target concentration (RTC) were calculated for each trimester or for each month. RTCs were compared between patients with and without an increase in the frequency of seizures. A receiver operating characteristic curve to determine the RTC threshold, which predicts increased seizure frequency best, was drawn. Results A total of 12 patients and their 12 pregnancies were reviewed retrospectively. AC increased by 82.5% during the first trimester (p = 0.0343), 203.2% during the second trimester (p = 0.0010), and 197.0% during the third trimester (p = 0.0061) compared with the prepregnancy level. The value returned to the prepregnancy level after delivery. Seven patients who had adequate baseline information were included to examine the association between serum LTG concentration and seizure frequency. The RTC values of patients with and without an increased frequency of seizures were significantly different (p = 0.0164), and increased seizure frequency was associated with a lower RTC. An RTC < 0.64 was a predictor of deteriorating seizures. Conclusions The pharmacokinetic changes in LTG during pregnancy displayed marked interpatient variation. TDM can support a rational treatment plan for LTG use during pregnancy. We recommend regular monitoring of LTG serum concentrations from prepregnancy to postpartum.

Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy

“…A noticeable pharmacokinetic change in LTG during pregnancy is attributed to estrogen‐induced glucuronidation and increased renal blood flow, 13 making it challenging to stabilize plasma levels during pregnancy 14 . Previous studies have shown that apparent oral clearance of LTG in the second trimester and third trimester almost doubled, and total blood drug concentration decreased by 40%–60%, compared to that of the nonpregnant baseline 10,15 . In this study, the maximal clearance of LTG increased by 3.42 times, and the mean blood drug levels decreased by 57% in the second trimester (Figures 2 and 3).…”

“…Pennell et al recommended monthly monitoring of AED levels during pregnancy, with the possible exception of carbamazepine (CBZ) due to the clearance and dose being virtually unchanged 3 . Some studies suggested a dosage adjustment if an AED level decreased by 15%–25% that of the nonpregnant target concentration, especially for pregnancies with risk factors of convulsions 9,10 . Currently, available data on pharmacokinetics changes correlated with pregnancy and dosage adjustments guided by TDM for newer AEDs are insufficient, especially for LEV and OXC.…”

Understanding and Responding to Prescribing Patterns of Sodium Valproate-Containing Medicines in Pregnant Women and Women of Childbearing Age in Western Cape, South Africa

“…This is probably because the older South African national treatment guidelines recommended VPA and lamotrigine as first-line treatments for epilepsy and mood disorders in women receiving ART, driven by concerns of pharmacokinetic interactions between AEDs and antiretroviral agents (including dolutegravir, which has recently been introduced as part of first-line HIV treatment in South Africa) [ 20 , 34 ]. Although lamotrigine is the other recommended agent for WOCBA and pregnant women, the complicated initiation regimen, the need for intensive therapeutic drug monitoring particularly during the pregnancy and after delivery [ 35 ], and concerns regarding the risk of severe skin reactions, has contributed to the preferential prescribing of VPA in this population. Only 9% of women who experienced a pregnancy in that year and who were taking any type of AED/MSM were exposed to lamotrigine, compared with 45–47% who were exposed to VPA (Table 4 ).…”

Affective disorders: A question of continuing treatment during pregnancy (Review)

“…The metabolization of lamotrigine occurs in the liver and the enzymes responsible for this process are induced by pregnancy (69). So, lamotrigine clearance increases progressively and in order to maintain a therapeutic drug concentration, a dose increase is required (70). This change of the dose should be guided by clinical response.…”