Labetalol Dosing in Pregnancy: PBPK/PD and CYP2C19 Polymorphisms.
J Clin Pharmacol
; 2024 07 08.
Article
en En
| MEDLINE
| ID: mdl-38973651
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
J Clin Pharmacol
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Reino Unido