Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882.
Eur J Clin Pharmacol
; 70(6): 675-84, 2014 Jun.
Article
en En
| MEDLINE
| ID: mdl-24728182
ABSTRACT
PURPOSE:
ACT-178882, a direct renin inhibitor, was used as a model compound in an elaborate drug-drug interaction study with atorvastatin and simvastatin to explore complex CYP3A4 inductive and inhibitory properties.METHODS:
Thirty-two healthy male subjects received single doses of 20 mg atorvastatin and 20 mg simvastatin on days 1, 9, 31, and 41. On days 6 to 33, 500 mg ACT-178882 was administered once daily. Plasma concentrations of ACT-178882, simvastatin, and atorvastatin were measured by LC-MS/MS. Routine safety assessments were performed throughout the study.RESULTS:
Exposure (as based on area under the curve) to simvastatin and 6ß-hydroxyacid simvastatin increased (90 % confidence interval) 4.63-fold (3.90, 5.50) and 3.71-fold (3.19, 4.32), respectively, when comparing day 9 and day 1. On day 9, exposure to atorvastatin was similar but Cmax decreased, while both variables decreased for ortho-hydroxy atorvastatin when compared to day 1. On day 31, after prolonged administration of ACT-178882, exposure to atorvastatin, ortho-hydroxy atorvastatin, simvastatin, and 6ß-hydroxyacid simvastatin decreased by 14, 19, 21, and 27 %, respectively, when compared to day 9. However, on this day, exposure to simvastatin and its metabolite was still markedly higher when compared to day 1. Effects of ACT-178882 had largely dissipated on day 41.CONCLUSIONS:
This design enabled the study of complex time-dependent effects on CYP3A4 activity with clinically relevant substrates.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piridinas
/
Inhibidores de Hidroximetilglutaril-CoA Reductasas
/
Ciclopropanos
/
Citocromo P-450 CYP3A
/
Inductores del Citocromo P-450 CYP3A
/
Inhibidores del Citocromo P-450 CYP3A
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Eur J Clin Pharmacol
Año:
2014
Tipo del documento:
Article