Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age

Karanam, Ashwin; Pennell, Page B.; French, Jacqueline A.; Harden, Cynthia L.; Allien, Stephanie; Lau, Connie; Barnard, Sarah; Callisto, Samuel P.; Birnbaum, Angela K.

doi:10.1002/ana.25321

Cited by 30 publications

(28 citation statements)

References 27 publications

(39 reference statements)

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“…The monitoring frequency of this study was once every 1–3 months. Recent studies show that increases in LTG clearance can begin as early as 5 weeks GA, often before women know they are pregnant (Karanam et al, ). Many doctors and patients in China have not paid sufficient attention to TDM during pregnancy, leading to missing baseline or early concentrations.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy

et al. 2019

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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.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy

et al. 2019

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“…A formal pharmacokinetic modelling analysis demonstrated two subpopulations, one with 23% of women who had only a 20% increase in lamotrigine clearance and another with 77% of women who had a 220% increase in clearance, hypothesized to be due to pharmacogenetic differences (Polepally et al, 2014). A recent study with frequent sampling, beginning prior to pregnancy and through the first trimester, highlighted that clearance changes are measurable as early as the third week after conception and clearance increases by an average of 50% by the end of the first trimester (Karanam et al, 2018). These findings underscore the importance of performing therapeutic drug monitoring when available and beginning early in pregnancy.…”

Section: Pharmacokinetic Changes During Pregnancymentioning

confidence: 99%

“…Counselling of the patient should reinforce the need for AEDs, and any potential AED risk to the foetus should be balanced against the risk of increased seizures to both the mother and the developing foetus (see Maternal and foetal risks associated with seizures). If the woman is taking an AED that undergoes substantial clearance changes (table 2) and if drug levels are obtainable, it is ideal to determine a blood level Management of epilepsy in pregnancy by the mid first trimester given the early gestational changes during clearance that occur for many of the common AEDs used during pregnancy (Karanam et al, 2018;Voinescu et al, 2018). The individualized target concentration should be reassessed and maintained during pregnancy with blood levels throughout pregnancy (Harden et al, 2009a).…”

Section: Optimal Management During Pregnancy Delivery and Postpartummentioning

confidence: 99%

Executive Summary: Management of epilepsy in pregnancy: A report from the International League Against Epilepsy Task Force on Women and Pregnancy

et al. 2019

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“…[20][21][22] Additionally, many AEDs, such as lamotrigine and levetiracetam, have variable pharmacokinetics during pregnancy and the early postpartum period, which could complicate assessment of exposure via breastfeeding. [23][24][25][26][27] Some studies have focused on breast milk concentrations as surrogate markers for actual AED concentrations in children. 28,29 However, breast milk concentrations do not take into account differences in infant pharmacokinetic processes, such as absorption, ontogeny of metabolic and elimination profiles, [30][31][32][33][34][35] or the timing of sampling with respect to the mother's dose of AEDs.…”

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confidence: 99%

Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

et al. 2020

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There is limited information on infant drug exposure via breastfeeding by mothers who are receiving antiepileptic drug therapy.OBJECTIVE To provide direct, objective information on antiepileptic drug exposure through breast milk.DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study was conducted between December 2012 to October 2016, with follow-up in children until 6 years of age at 20 sites across the United States. Data were collected via an observational multicenter investigation (Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs [MONEAD]) of outcomes in pregnant mothers with epilepsy and their children. Pregnant women with epilepsy who were aged 14 to 45 years, had pregnancies that had progressed to less than 20 weeks' gestational age, and had measured IQ scores of more than 70 points were enrolled and followed up through pregnancy and 9 postpartum months. Their infants were enrolled at birth. Data were analyzed from May 2014 to August 2019.EXPOSURES Antiepileptic drug exposure in infants who were breastfed. MAIN OUTCOMES AND MEASURESThe percentage of infant-to-mother concentration of antiepileptic drugs. Antiepileptic drug concentrations were quantified from blood samples collected from infants and mothers at the same visit, 5 to 20 weeks after birth. Concentrations of antiepileptic drugs in infants at less than the lower limit of quantification were assessed as half of the lower limit. Additional measures collected were the total duration of all daily breastfeeding sessions and/or the volume of pumped breast milk ingested from a bottle.RESULTS A total of 351 women (of 865 screened and 503 eligible individuals) were enrolled, along with their 345 infants (179 female children [51.9%]; median [range] age, 13 [5-20] weeks). Of the 345 infants, 222 (64.3%) were breastfed; the data collection yielded 164 matching infant-mother concentration pairs from 138 infants. Approximately 49% of all antiepileptic drug concentrations in nursing infants were less than the lower limit of quantification. The median percentage of infant-to-mother concentration for all 7 antiepileptic drugs and 1 metabolite (carbamazepine, carbamazepine-10,11-epoxide, levetiracetam, lamotrigine, oxcarbazepine, topiramate, valproate, and zonisamide) ranged from 0.3% (range, 0.2%-0.9%) to 44.2% (range, 35.2%-125.3%). In multiple linear regression models, maternal concentration was a significant factor associated with lamotrigine concentration in infants (Pearson correlation coefficient, 0.58; P < .001) but not levetiracetam concentration in infants.CONCLUSIONS AND RELEVANCE Overall, antiepileptic drug concentrations in blood samples of infants who were breastfed were substantially lower than maternal blood concentrations. Given the well-known benefits of breastfeeding and the prior studies demonstrating no ill effects when the mother was receiving antiepileptic drugs, these findings support the breastfeeding of infants by mothers with epilepsy who are taking antiepileptic drug therapy.

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Lamotrigine clearance increases by 5 weeks gestational age: Relationship to estradiol concentrations and gestational age

Cited by 30 publications

References 27 publications

Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy

Pharmacokinetic changes and therapeutic drug monitoring of lamotrigine during pregnancy

Executive Summary: Management of epilepsy in pregnancy: A report from the International League Against Epilepsy Task Force on Women and Pregnancy

Antiepileptic Drug Exposure in Infants of Breastfeeding Mothers With Epilepsy

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