title: Investigation of combined CYP3A4 inductive/inhibitory properties by studying statin interactions: a model study with the renin inhibitor ACT-178882.
abstract: OBJECTIVE
  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 6β-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 6β-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.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland, jasper.dingemanse@actelion.com.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
authors.forename: Laurent B
authors.initials: LB
authors.lastname: Nicolas
authors.forename: Luc
authors.initials: L
authors.lastname: van Bortel
mesh_terms: D000293:Adolescent; D000328:Adult; D000069059:Atorvastatin; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000378:metabolism*; D065701:Cytochrome P-450 CYP3A Inducers / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D004347:Drug Interactions; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D019821:Simvastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D003521:Cyclopropanes; D065701:Cytochrome P-450 CYP3A Inducers; D065692:Cytochrome P-450 CYP3A Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C571787:MK-1597
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