Labetalol Dosing in Pregnancy: PBPK/PD and CYP2C19 Polymorphisms

Area of Science:

• Pharmacokinetics and Pharmacodynamics
• Computational Modeling
• Genetics

Background:

• Limited pharmacokinetic data exists for labetalol in pregnant individuals.
• Understanding labetalol's behavior in pregnancy is crucial for managing hypertension.
• CYP2C19 genotype influences drug metabolism and may affect labetalol's efficacy.

Purpose of the Study:

• To develop a physiologically based pharmacokinetic (PBPK) model for labetalol in non-pregnant individuals, considering CYP2C19 genotypes.
• To adapt the PBPK model for pregnant individuals in the second and third trimesters.
• To integrate the PBPK model with a pharmacodynamic (PD) model to predict labetalol's blood pressure-lowering effects during pregnancy.

Main Methods:

• Constructed a PBPK model for labetalol incorporating CYP2C19 genotypes (*1/*1, *1/*2 or *3, *2/*2, *17/*17).
• Validated the model against clinical data from scientific literature for non-pregnant and pregnant populations.
• Combined the pregnancy PBPK model with a previously established PD model.

Main Results:

• The non-pregnant PBPK model showed good agreement with observed data (Cmax, Tmax, AUC ratios near 1).
• The pregnancy PBPK model adequately captured observed pharmacokinetics, though clearance was slightly underestimated.
• Labetalol exposure varied by CYP2C19 genotype in pregnancy, with *2/*2 alleles showing similar exposure to controls, while others had increased exposure.

Conclusions:

• Physiologically based pharmacokinetic/pharmacodynamic modeling provides valuable insights into labetalol use during pregnancy.
• While labetalol exposure differs across CYP2C19 genotypes in pregnant individuals, its blood pressure-lowering effect is comparable.
• Close patient monitoring is recommended due to inter-individual variability and potential blood pressure changes in pregnancy.