title: Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study.
abstract: OBJECTIVE
  Danoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) 3A. Clinical studies in HCV patients have shown a potential need for a high danoprevir daily dose and/or dosing frequency. Ritonavir, an HIV-1 protease inhibitor (PI) and potent CYP3A inhibitor, is used as a pharmacokinetic enhancer at subtherapeutic doses in combination with other HIV PIs. Coadministering danoprevir with ritonavir as a pharmacokinetic enhancer could allow reduced danoprevir doses and/or dosing frequency. Here we evaluate the impact of ritonavir on danoprevir pharmacokinetics.
  
  
  METHODS
  The effects of low-dose ritonavir on danoprevir pharmacokinetics were simulated using Simcyp, a population-based simulator. Following results from this drug-drug interaction (DDI) model, a crossover study was performed in healthy volunteers to investigate the effects of acute and repeat dosing of low-dose ritonavir on danoprevir single-dose pharmacokinetics. Volunteers received a single oral dose of danoprevir 100 mg in a fixed sequence as follows: alone, and on the first day and the last day of 10-day dosing with ritonavir 100 mg every 12 hours.
  
  
  RESULTS
  The initial DDI model predicted that following multiple dosing of ritonavir 100 mg every 12 hours for 10 days, the danoprevir area under the plasma concentration-time curve (AUC) from time zero to 24 hours and maximum plasma drug concentration (C(max)) would increase by about 3.9- and 3.2-fold, respectively. The clinical results at day 10 of ritonavir dosing showed that the plasma drug concentration at 12 hours postdose, AUC from time zero to infinity and C(max) of danoprevir increased by approximately 42-fold, 5.5-fold and 3.2-fold, respectively, compared with danoprevir alone. The DDI model was refined with the clinical data and sensitivity analyses were performed to better understand factors impacting the ritonavir-danoprevir interaction.
  
  
  CONCLUSIONS
  DDI model simulations predicted that danoprevir exposures could be successfully enhanced with ritonavir coadministration, and that a clinical study confirming this result was warranted. The clinical results demonstrate that low-dose ritonavir enhances the pharmacokinetic profile of low-dose danoprevir such that overall danoprevir exposures can be reduced while sustaining danoprevir trough concentrations.
authors.affiliation: Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA. micaela.reddy@roche.com
authors.forename: Micaela B
authors.initials: MB
authors.lastname: Reddy
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Joshua O
authors.initials: JO
authors.lastname: Haznedar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fretland
authors.forename: Steven
authors.initials: S
authors.lastname: Blotner
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
mesh_terms: D000328:Adult; D003198:Computer Simulation; D018592:Cross-Over Studies; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000097:blood / Q000493:pharmacokinetics*; D047029:Lactams, Macrocyclic; D008297:Male; D008954:Models, Biological; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019438:Ritonavir / Q000494:pharmacology*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011392:Proline; D011480:Protease Inhibitors; D019438:Ritonavir; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C553752:danoprevir