Bhamidipaty-Pelosi Surya, Muralidharan Suhaas, Yeley Brittany C, Haas David M, Quinney Sara K
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Department of Pharmacy Practice, Purdue University College of Pharmacy, West Lafayette, IN 47907, USA.
J Clin Med. 2025 Apr 18;14(8):2793. doi: 10.3390/jcm14082793.
Hypertensive disorders of pregnancy are a leading cause of pregnancy-related deaths in the United States, accounting for 7% of maternal mortality. Labetalol and nifedipine are the first-line drugs for the management of hypertension in pregnancy, but there are little data guiding the choice of one drug over the other. The current pilot longitudinal study aims to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of labetalol stereoisomers throughout pregnancy and postpartum. This is a single-center clinical study recruiting up to 40 pregnant individuals ≥ 18 years of age at the time of enrollment, taking labetalol as per the standard of care. The exclusion criteria include any pathophysiology impacting the PK of labetalol, e.g., liver failure. Maternal plasma, urine, amniotic fluid, cord blood, and breast milk will be collected, and labetalol stereoisomers will be measured using a validated LC-MS/MS assay. Heart rate and blood pressure will be measured as the PD endpoints. These may be assessed throughout a participant's dosing interval at scheduled PK study visits, which will occur every 6-10 weeks during pregnancy, at delivery, during the 1st week postpartum, and up to 20 weeks postpartum. The primary aim is to characterize the PK and PD of labetalol during pregnancy and in the postpartum period. The secondary aim is to determine the extent of breast milk excretion of and infant exposure to labetalol from breast milk. The data will be analyzed using population PK modeling to evaluate the PK/PD relationship and ultimately develop trimester-specific dosing recommendations. To our knowledge, this is the first study aiming to characterize the PK of labetalol stereoisomers across pregnancy and postpartum, utilizing individual stereoisomer data to evaluate the PK/PD relationship, and collecting postpartum samples, including breast milk, to model infant exposure to labetalol through breast milk. This study will provide important PK/PD data and knowledge which will be combined with large multi-center clinical trial data to develop trimester-specific dosing regimens for anti-hypertensive agents.
妊娠期高血压疾病是美国妊娠相关死亡的主要原因，占孕产妇死亡率的7%。拉贝洛尔和硝苯地平是妊娠期高血压管理的一线药物，但几乎没有数据指导选择其中一种药物而非另一种。当前的纵向试点研究旨在描述拉贝洛尔立体异构体在整个孕期及产后的药代动力学（PK）和药效动力学（PD）特征。这是一项单中心临床研究，招募最多40名在入组时年龄≥18岁的孕妇，她们按照护理标准服用拉贝洛尔。排除标准包括任何影响拉贝洛尔PK的病理生理学情况，例如肝功能衰竭。将收集母体血浆、尿液、羊水、脐带血和母乳，并使用经过验证的液相色谱 - 串联质谱法（LC-MS/MS）测定拉贝洛尔立体异构体。将测量心率和血压作为PD终点。这些指标可在参与者的给药间隔期间，在预定的PK研究访视时进行评估，这些访视将在孕期每6 - 10周、分娩时、产后第1周以及产后长达20周进行。主要目的是描述拉贝洛尔在孕期和产后的PK和PD特征。次要目的是确定拉贝洛尔在母乳中的排泄程度以及婴儿通过母乳接触拉贝洛尔的情况。将使用群体PK建模分析数据，以评估PK/PD关系，并最终制定针对不同孕期的给药建议。据我们所知，这是第一项旨在描述拉贝洛尔立体异构体在孕期及产后的PK特征、利用个体立体异构体数据评估PK/PD关系，并收集包括母乳在内的产后样本以模拟婴儿通过母乳接触拉贝洛尔的研究。这项研究将提供重要的PK/PD数据和知识，这些数据和知识将与大型多中心临床试验数据相结合，以制定针对不同孕期的抗高血压药物给药方案。
