title: Almorexant effects on CYP3A4 activity studied by its simultaneous and time-separated administration with simvastatin and atorvastatin.
abstract: OBJECTIVE
  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 (AUC0-∞) 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 Cmax [3.7 (3.0, 4.5) for both doses]. Time-separated administration resulted in relevant reductions of the interaction [AUC0-∞: 1.4 (1.2, 1.7) (100 mg), 1.7 (1.5, 2.0) (200 mg); Cmax: 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, AUC0-∞ and Cmax of atorvastatin increased (ratios ranged from 1.1 to 1.5). AUC0-∞ and Cmax of o-hydroxy atorvastatin decreased dose-independently [AUC0-∞: 0.8 (0.8, 0.9) (100 mg), 0.6 (0.5, 0.6) (200 mg); Cmax: 0.3 (0.3, 0.4) (100 mg), 0.2 (0.2, 0.3) (200 mg)] when atorvastatin was concomitantly administered. Cmax of o-hydroxy atorvastatin slightly decreased (0.8 for both doses) following time-separated administration; AUC0-∞ 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.
authors: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland. matthias.hoch@actelion.com
authors: Matthias
authors: M
authors: Hoch
authors: Petra
authors: P
authors: Hoever
authors: Rudolf
authors: R
authors: Theodor
authors: Jasper
authors: J
authors: Dingemanse
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D000069059:Atorvastatin; D001711:Biotransformation; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005858:Germany; D006207:Half-Life; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D006900:Hydroxylation; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D007546:Isoquinolines / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000081:Acetamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006993:Hypnotics and Sedatives; D007546:Isoquinolines; D011758:Pyrroles; C519150:almorexant; D000069059:Atorvastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human