Abstract：
As detailed information on the pharmacokinetics (PK) of labetalol in pregnant people are lacking, the aims of this study were: (1) to build a physiologically based PK (PBPK) model of labetalol in non-pregnant individuals that incorporates different CYP2C19 genotypes (specifically, *1/*1, *1/*2 or *3, *2/*2, and *17/*17); (2) to translate this model to the second and third trimester of pregnancy; and (3) to combine the model with a previously published direct pharmacodynamic (PD) model to predict the blood pressure lowering effect of labetalol in the third trimester. Clinical data for model evaluation was obtained from the scientific literature. In non-pregnant populations, the mean ratios of simulated versus observed peak concentration (Cmax), time to reach Cmax (Tmax), and exposure (area under the plasma concentration-time curve, AUC) were 0.94, 0.82, and 1.16, respectively. The pregnancy PBPK model captured the observed PK adequately, but clearance was slightly underestimated with mean ratios of simulated versus observed Cmax, Tmax, and AUC of 1.28, 1.30, and 1.39, respectively. The results suggested that pregnant people with CYP2C19 *2/*2 alleles have similar labetalol exposure and trough levels compared to non-pregnant controls, whereas those with other alleles were found to have increased exposure and trough concentrations. Importantly, the pregnancy PBPK/PD model predicted that, despite increased exposure in some genotypes, the blood pressure lowering effect was broadly comparable across all genotypes. In view of the large inter-individual variability and the potentially increasing blood pressure during pregnancy, patients may need to be closely monitored for achieving optimal therapeutic effects and avoiding adverse events.
摘要：
由于缺乏拉贝洛尔在孕妇中的药代动力学（PK）的详细信息，这项研究的目的是：（1）在非妊娠个体中建立一个基于生理的PK（PBPK）模型，该模型包含不同的CYP2C19基因型（特别是，*1/*1，*1/*2或*3，*2/*2和*17/*17）；（2）将该模型转换为妊娠的第二和第三三个月；（3）将该模型与先前发表的直接药效学（PD）模型相结合，以预测拉贝洛尔在妊娠晚期的降血压作用。用于模型评估的临床数据来自科学文献。在非怀孕人群中，模拟峰浓度与观察峰浓度的平均比值(Cmax)，达到Cmax的时间（Tmax），和暴露（血浆浓度-时间曲线下的面积，AUC）分别为0.94、0.82和1.16。妊娠PBPK模型充分捕获了观察到的PK，但模拟与观察到的Cmax的平均比值略为低估了清除率，Tmax,AUC分别为1.28、1.30和1.39。结果表明，与未怀孕的对照组相比，CYP2C19*2/*2等位基因的孕妇具有相似的拉贝洛尔暴露和波谷水平。而那些与其他等位基因被发现有增加的暴露和谷浓度。重要的是,妊娠PBPK/PD模型预测，尽管某些基因型的暴露增加，所有基因型的血压降低效果大致相当.鉴于个体间的差异很大，并且在怀孕期间可能会增加血压，患者可能需要密切监测,以达到最佳治疗效果并避免不良事件.
