妊娠期拉莫三嗪血药浓度变化及与发作频率相关性研究

Changes of Serum Lamotrigine Concentration during Pregnancy and Its Correlation with Epileptic Seizure Frequency

目的表征拉莫三嗪从孕前到产后晚期的完整药动学变化,评价妊娠期拉莫三嗪血药浓度变化与发作频率的相关性,确定妊娠期癫痫发作预测指标。方法回顾性收集2016年1月~2019年11月就诊于中国医科大学附属盛京医院神经内科门诊单用拉莫三嗪并定期进行血药浓度监测的妊娠期癫痫妇女临床病历资料,计算不同妊娠分期拉莫三嗪的表观清除率(CL/F)及拉莫三嗪血药浓度与孕前靶浓度的比值(the ratio to target concentration,RTC),通过比较有或无癫痫发作频率增加患者组间RTC值的差异,评价妊娠期拉莫三嗪血药浓度与发作频率间的相关性,并运用受试者工作特征曲线(ROC曲线)确定可预测妊娠期癫痫发作频率增加的RTC阈值。结果对23例单用拉莫三嗪治疗的妊娠期癫痫患者282次血药浓度监测的回顾性分析表明,与孕前基线值相比,拉莫三嗪CL/F在妊娠早期(P=0.0014)、妊娠中期(P<0.0001)及妊娠晚期(P<0.0001)分别增加了105.23%、202.85%和201.11%,分娩当日CL/F迅速下降,于产后6周可逐渐恢复至孕前水平。通过t检验比较有或无癫痫发作频率增加的患者RTC值,两组间RTC均值存在显著差异(P<0.0001),提示孕期癫痫发作频率增加与较低的RTC值有关。利用ROC曲线确定妊娠期癫痫发作频率增加的RTC阈值为0.62,敏感性为65.79%,特异性为81.40%。结论妊娠期拉莫三嗪药动学特征变化显著,当妊娠期拉莫三嗪血药浓度降低至孕前靶浓度的62%时提示癫痫发作风险增加,血药浓度监测可为妊娠期拉莫三嗪治疗方案调整提供依据。

OBJECTIVE To evaluate the pharmacokinetic changes of lamotrigine from pre-pregnancy to postpartum in a Chinese population,to assess the correlation between the changes of serum lamotrigine concentration during pregnancy and epileptic seizure frequency,and to determine the predictors of the increased seizure frequency during pregnancy.METHODS The clinical records of pregnant women with epilepsy who were treated with lamotrigine monotherapy and had regular therapeutic drug monitoring in the Department of Neurology,Shengjing Hospital of China Medical University from January 2016 to November 2019 were collected.The apparent clearance(CL/F)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 to evaluate the correlation between the changes of serum lamotrigine concentration during pregnancy and epileptic seizure frequency.A receiver operating characteristic(ROC)curve was drawn to determine the threshold of RTC and to predict the increased seizure frequency.RESULTS A total of 23 patients contributing to 282 blood samples were reviewed retrospectively.CL/F increased by 105.23%during the first trimester(P=0.0014),202.85%during the second trimester(P<0.0001),and 201.11%during the third trimester(P<0.0001)compared with the pre-pregnancy level.The value decreased rapidly on the day of delivery and gradually returned to the pre-pregnancy level at 6 weeks after delivery.Ten patients who had adequate baseline information were included to examine the association between serum lamotrigine concentration and seizure frequency.The RTC values of patients with and without an increased seizure frequency were significantly different(P<0.0001),and increased seizure frequency was associated with a lower RTC.An RTC<0.62 was a predictor of deteriorating seizures.CONCLUSION The pharmacokinetic changes in lamotrigine during pregnancy display significant inter-individual variation.Constant vigilance is necessary in order to avoid epileptic seizures for women with epilepsy on lamotrigine monotherapy during pregnancy when the lamotrigine serum concentration is less than 62%of the target concentration.Therapeutic drug monitoring can support a rational treatment plan for lamotrigine use during pregnancy.