title: Pharmacokinetics of a three-way drug interaction between danoprevir, ritonavir and the organic anion transporting polypeptide (OATP) inhibitor ciclosporin.
abstract: BACKGROUND
  Danoprevir (RG7227) is a potent macrocyclic inhibitor of the hepatitis C virus NS3/4A protease, which is currently in development in combination with low-dose ritonavir for the treatment of chronic hepatitis C infection. Danoprevir is a substrate of cytochrome P450 3A4, and the organic anion transporting polypeptides (OATP) 1B1 and 1B3.
  
  
  OBJECTIVE
  The objective of this study was to evaluate the effect of a potent OATP inhibitor, ciclosporin, on danoprevir pharmacokinetics, when administered as danoprevir/ritonavir. The effect of danoprevir/ritonavir on ciclosporin pharmacokinetics was also investigated.
  
  
  METHODS
  This was a single-dose, randomized, open-label, two-sequence, three-period, crossover study in healthy volunteers. In the first period, subjects were randomized to receive either a single oral dose of danoprevir 100 mg in combination with ritonavir 100 mg or a single oral dose of ciclosporin 100 mg. After a 14-day washout, patients were crossed over to receive the opposite treatment. In period 3, all subjects received the combination of danoprevir/ritonavir and ciclosporin following a 14-day washout from period 2. Blood samples were collected serially with each dose for pharmacokinetic assessment. Pharmacokinetic parameters were estimated using non-compartmental analysis. Geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) were used to compare pharmacokinetic parameters [maximum concentration (C max), area under the concentration-time curve from time zero to infinity (AUC∞), and concentration 12 h post-dose (C 12h)] of danoprevir/ritonavir and ciclosporin when administered alone or in combination. Measures of safety and tolerability were also evaluated.
  
  
  RESULTS
  A total of 18 subjects were enrolled, and 17 completed the study. The C max, AUC∞, and C 12h GMRs (90 % CI) when danoprevir/ritonavir and ciclosporin were co-administered versus danoprevir/ritonavir or ciclosporin alone were 7.22 (5.42-9.62), 13.6 (11.2-16.6), and 22.5 (17.4-29.3), respectively, for danoprevir, 1.97 (1.72-2.27), 2.23 (2.07-2.42), and 2.50 (2.22-2.81), respectively, for ritonavir, and 1.42 (1.29-1.57), 3.65 (3.27-4.08), and 6.15 (5.32-7.11), respectively, for ciclosporin. All treatments were well tolerated, with no laboratory abnormalities, and no clinically significant changes in vital signs, electrocardiograms, or physical examinations observed.
  
  
  CONCLUSIONS
  A significant drug-drug interaction was observed between ciclosporin and danoprevir/ritonavir, leading to substantial increases in exposure to danoprevir and a lesser impact on exposure to ritonavir. Therefore, co-administration of danoprevir/ritonavir with potent OATP inhibitors should be undertaken with appropriate precautions.
authors.affiliation: Pharma Research and Early Development, Department of Clinical Pharmacology, Hoffmann-La Roche Inc, 340 Kingsland Street, Nutley, NJ 07110, USA. barbara.brennan@roche.com
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Brennan
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Moreira
authors.forename: Peter N
authors.initials: PN
authors.lastname: Morcos
authors.forename: Mercidita T
authors.initials: MT
authors.lastname: Navarro
authors.forename: Jiney
authors.initials: J
authors.lastname: Asthappan
authors.forename: Petra
authors.initials: P
authors.lastname: Goelzer
authors.forename: Paul
authors.initials: P
authors.lastname: Weigl
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
mesh_terms: D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016466:CHO Cells; D003412:Cricetulus; D018592:Cross-Over Studies; D003521:Cyclopropanes; D016572:Cyclosporine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D006801:Humans; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D047029:Lactams, Macrocyclic; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives; D019438:Ritonavir / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D016572:Cyclosporine; C553752:danoprevir; D011392:Proline; D019438:Ritonavir