Pharmacokinetic Characterization of Labetalol in Pregnancy (The CLIP Study): A Prospective Observational Longitudinal Pharmacokinetic/Pharmacodynamic Cohort Study During Pregnancy and Postpartum

Abstract

Background/Objectives: 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. Methods: 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. Results/Conclusions: 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.

Keywords: chiral LC-MS/MS; hypertensive disorders of pregnancy; labetalol; population PK/PD model; protocol.

Figure 1

Inclusion criteria and study visit timing. The figure displays the inclusion and exclusion criteria for this study and the three timepoints for the PK study visits. Antenatal PK sampling is anticipated to occur during each trimester, with 6–10 weeks between visits. Postpartum sampling will be up to 20 weeks post-delivery.

Figure 2

Clinical study visit flow. This figure displays the flow of activities during a clinical PK study visit, beginning with the recording of vital signs, blood draws, and other specimen collection (with breast milk collection only during the postpartum visit).