Target-Mediated Population Pharmacokinetic Modeling of Endothelin Receptor Antagonists.
Pharm Res
; 37(1): 2, 2019 Dec 10.
Article
en En
| MEDLINE
| ID: mdl-31823033
ABSTRACT
PURPOSE:
Bosentan, clazosentan, and tezosentan are three small-molecule endothelin receptor antagonists (ERAs), displacing endothelin-1 (ET-1) from its binding site. A target-mediated drug disposition (TMDD) pharmacokinetic (PK) model described the non-linearity in the PK of bosentan caused by its high receptor binding affinity with time-dependent varying receptor expression or reappearance. The aim of this analysis was to investigate the presence of TMDD for clazosentan and tezosentan and to corroborate the hypothesis of a diurnal receptor synthesis.METHODS:
PK data from healthy subjects after intravenous (i.v.) administration of single ascending doses of bosentan, clazosentan, and tezosentan were analyzed. Frequent blood samples for PK measurements were collected. Population analyses, simulations, and evaluations were performed using a non-linear mixed-effects modeling approach.RESULTS:
Two-compartment TMDD models were successfully developed describing the PK of all three ERAs with different receptor-complex internalization properties. The observed multiple peaks in the concentration-time profiles were captured with cosine functions on the receptor synthesis rate mimicking a diurnal receptor expression or reappearance. The results strongly suggest that TMDD is a class effect of ERAs.CONCLUSION:
The developed TMDD PK models are a next step towards understanding the complex PK of ERAs and further support the hypothesis that TMDD is a class effect of ERAs.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Piridinas
/
Pirimidinas
/
Sulfonamidas
/
Tetrazoles
/
Receptores de Endotelina
/
Dioxanos
/
Antagonistas de los Receptores de Endotelina
/
Bosentán
/
Modelos Biológicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
/
Male
Idioma:
En
Revista:
Pharm Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania