title: Two-way interaction study between ritonavir boosted danoprevir, a potent HCV protease inhibitor, and ketoconazole in healthy subjects.
abstract: BACKGROUND
  Danoprevir is a potent, highly selective, macrocyclic, orally bioavailable inhibitor of the hepatitis C virus protease, and a substrate of cytochrome P450 (CYP) 3A. It is co-administered with low-dose ritonavir, a potent CYP3A inhibitor, to enhance danoprevir pharmacokinetics. Ketoconazole is a substrate for and potent selective inhibitor of CYP3A.
  
  
  METHODS
  In this open-label, 3-period study, the 2-way interaction potential between ritonavir-boosted danoprevir (danoprevir/r) and ketoconazole was investigated in 18 healthy subjects. Subjects initially received ketoconazole 200 mg q24h for 4 days (Period 1) followed by a 7-day washout period. Danoprevir/r 100/100 mg q12h was then given for 10 days (Period 2) followed by a further 4 days of danoprevir/r 100/100 mg q12h plus ketoconazole 200 mg q24h (Period 3). Serial blood samples were collected for the determination of danoprevir, ritonavir and/or ketoconazole plasma concentrations, and calculation of pharmacokinetic parameters. Safety and tolerability were monitored throughout the study.
  
  
  RESULTS
  Co-administration of ketoconazole with danoprevir/r modestly increased the danoprevir AUCτ by 1.44-fold, with no effect on danoprevir Cmax. Co-administration of danoprevir/r with ketoconazole substantially increased ketoconazole AUCτ and Cmax by 3.71-fold and 1.73-fold, respectively. Danoprevir/r was well tolerated when administered alone or with ketoconazole.
  
  
  CONCLUSIONS
  These results indicate that the effect of potent CYP3A inhibitors, such as ketoconazole, on danoprevir/r pharmacokinetics is not likely to be clinically relevant.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Mercidita
authors.initials: M
authors.lastname: Navarro
authors.forename: Diana
authors.initials: D
authors.lastname: Chung
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
mesh_terms: D000328:Adult; D019540:Area Under Curve; D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D054833:Isoindoles; D007654:Ketoconazole / Q000494:pharmacology*; D007769:Lactams / Q000493:pharmacokinetics*; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D003521:Cyclopropanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D013449:Sulfonamides; C553752:danoprevir; D011392:Proline; D019438:Ritonavir; D007654:Ketoconazole