TIP-004 - CHARACTERIZATION OF LABETALOL IN PREGNANCY (THE CLIP STUDY).

S. Bhamidipaty-Pelosi¹, E. Cleary², D. Haas², S. Quinney³; ¹Indiana University, Indianapolis, Indiana, ²Indiana University, ³School of Medicine, Indiana University, Indianapolis, IN, USA.

Background: Labetalol and nifedipine are first line drugs for management of hypertension in pregnancy. Despite distinct pharmacologic profiles there are little data guiding pregnancy related pharmacokinetic (PK) changes and the choice of one drug over another. Understanding pregnancy related PK changes is critical for optimizing dosing recommendations. Labetalol is a racemic mixture of 4 stereoisomers, only 2 of which are active. It is likely that individual enantiomers undergo stereo-selective metabolism, leading to stereo-selective disposition. This pilot longitudinal study will characterize pharmacokinetics (PK) and pharmacodynamics (PD) of labetalol enantiomers antenatally and postpartum.

Methods: Forty pregnant individuals (≥18 years) receiving labetalol per standard of care will be recruited; individuals with known fetal anomalies or hepatic failure will be excluded. PK study visits will occur every 6-10 weeks throughout pregnancy and up to 10 weeks postpartum. At each visit, maternal plasma will be drawn prior to labetalol dosing and up to 6 hours post dose. Blood pressure and heart rate will be measured immediately before sample collection. At delivery, maternal blood, umbilical cord blood, and amniotic fluid will be collected. Neonate blood may be collected via heel-stick with clinical screen and at one time during the postpartum visit. Labetalol enantiomers will be analyzed using a validated chiral LC-MS/MS assay. DNA will be collected for future pharmacogenomics analyses. Population PK/PD (PopPK) modeling will determine labetalol PK/PD throughout pregnancy and postpartum and estimate infant exposure to labetalol through breast milk.

NOVELTY OF

Design: There is a paucity of clinically useful data on dose optimization in pregnancy as it relates to physiologic changes in PK. As a result, patients are often subtherapeutic or excessively managed. Optimizing management of hypertension in pregnancy is of critical importance due to the profound effects on uteroplacental flow which subsequently impacts the growing fetus.

To our knowledge, this is the first study to characterize PK of labetalol enantiomers across pregnancy and postpartum, utilize the individual enantiomer data to evaluate PK/PD relationships, and collect postpartum samples including breastmilk to model infant exposure to labetalol through breast milk.