Almorexant effects on CYP3A4 activity studied by its simultaneous and time-separated administration with simvastatin and atorvastatin.
PURPOSE: To characterise further the previously observed cytochrome P450 3A4 (CYP3A4) interaction of the dual orexin receptor antagonist almorexant. METHODS: Pharmacokinetic interactions were investigated (n = 14 healthy male subjects in two treatment groups) between almorexant at steady-state when administered either concomitantly or 2 h after administration of single doses of simvastatin (40 mg) or atorvastatin (40 mg). RESULTS: Almorexant dose-dependently increased simvastatin exposure (AUC(0-∞)) when administered concomitantly [geometric mean ratios (90 % CI): 2.5 (2.1, 2.9) (100 mg), 3.9 (3.3, 4.6) (200 mg)], but not C(max) [3.7 (3.0, 4.5) for both doses]. Time-separated administration resulted in relevant reductions of the interaction [AUC(0-∞): 1.4 (1.2, 1.7) (100 mg), 1.7 (1.5, 2.0) (200 mg); C(max): 1.5 (1.3, 1.9) (100 mg), 1.9 (1.6, 2.4) (200 mg)]. Similar results were obtained for hydroxyacid simvastatin. Independent of almorexant dose and relative time of administration, AUC(0-∞) and C(max) of atorvastatin increased (ratios ranged from 1.1 to 1.5). AUC(0-∞) and C(max) of o-hydroxy atorvastatin decreased dose-independently [AUC(0-∞): 0.8 (0.8, 0.9) (100 mg), 0.6 (0.5, 0.6) (200 mg); C(max): 0.3 (0.3, 0.4) (100 mg), 0.2 (0.2, 0.3) (200 mg)] when atorvastatin was concomitantly administered. C(max) of o-hydroxy atorvastatin slightly decreased (0.8 for both doses) following time-separated administration; AUC(0-∞) was unchanged. CONCLUSIONS: Whereas almorexant increased simvastatin exposure dose- and relative time of administration-dependently, atorvastatin exposure increased to a smaller extent and irrespective of dose and time. This suggests that the observed interaction of almorexant with simvastatin is mainly caused by intestinal CYP3A4 inhibition, whereas the interaction with atorvastatin is more due to hepatic CYP3A4 inhibition.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T2 T3 T4 T5 T6 T7 T8 T9
CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
simvastatin atorvastatin almorexant simvastatin atorvastatin Almorexant simvastatin hydroxyacid simvastatin almorexant Almorexant atorvastatin simvastatin atorvastatin orexin receptor CYP3A4 CYP3A4 cytochrome P450 3A4 CYP3A4 CYP3A4 o-hydroxy atorvastatin atorvastatin o-hydroxy atorvastatin almorexant almorexant simvastatin atorvastatin almorexant