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A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to evaluate the effects of danoprevir in combination with low-dose ritonavir (danoprevir/r) and placebo plus low-dose ritonavir on the pharmacokinetics of probe drugs for cytochrome P450 (CYP) 3A and CYP2C9, in patients with chronic hepatitis C.

Methods

A total of 54 patients infected with hepatitis C virus genotype 1 received an oral drug cocktail (2 mg midazolam, 10 mg warfarin and 10 mg vitamin K) before and after 14 days of dosing with either danoprevir/r or placebo plus low-dose ritonavir (placebo/r). Serial pharmacokinetic samples were collected up to 24 (midazolam) and 72 (S-warfarin) h post-dose. Plasma concentrations of midazolam, α-hydroxymidazolam and S-warfarin were measured using validated assays. Pharmacokinetic parameters were estimated using non-compartmental analysis, and geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) for the differences between baseline and post-dosing values were calculated.

Results

Danoprevir/r and placebo/r significantly increased midazolam area under the time–concentration curve (AUC0–∞) and reduced the midazolam metabolic ratio while S-warfarin AUC0–∞ was modestly decreased. When danoprevir data were pooled across doses, the midazolam GMR (90 % CI) AUC0–∞ was 9.41 (8.11, 10.9) and 11.14 (9.42, 13.2) following danoprevir/r and placebo/r dosing, respectively, and the S-warfarin GMR (90 % CI) AUC0–∞ was 0.72 (0.68, 0.76) and 0.76 (0.69, 0.85), respectively. The effects of danoprevir/r and placebo/r appeared to be qualitatively similar.

Conclusions

Substantial inhibition of CYP3A- and modest induction of CYP2C9- activity were observed with danoprevir/r and low-dose ritonavir.

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References

  1. Marcellin P, Roberts SK, Reddy KR, Harrison SA, Jensen DM, Hadziyannis S, Diago M, Weltman M, Messinger D, Tatsch F, Rizzetto M (2012) Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies. Expert Opin Drug Saf 11(6):901–909

    Article  PubMed  CAS  Google Scholar 

  2. Brennan BJ, Xu ZX, Grippo J (2013) Effect of peginterferon alfa-2a (40KD) on cytochrome P450 isoenzyme activity. Br J Clin Pharmacol 75(2):497–506

    Article  PubMed  CAS  Google Scholar 

  3. Gupta SK, Kolz K, Cutler DL (2011) Effects of multiple-dose pegylated interferon alfa-2b on the activity of drug-metabolizing enzymes in persons with chronic hepatitis C. Eur J Clin Pharmacol 67(6):591–599

    Article  PubMed  CAS  Google Scholar 

  4. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB, American Association for Study of Liver Diseases (2011) An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 54(4):1433–1444

    Article  PubMed  Google Scholar 

  5. Vertex Pharmaceuticals (2012) Incivek prescribing information. Vertex Pharmaceuticals, Cambridge. Available at: http://pi.vrtx.com/files/uspi_telaprevir.pdf. Accessed 23 July 2012

  6. Merck & Co. Inc. (2012) Victrelis prescribing information. Merck & Co. Inc., Whitehouse Station. Available at: http://www.merck.com/product/usa/pi_circulars/v/victrelis/victrelis_pi.pdf. Accessed 23 July 2012

  7. Kiser JJ, Burton JR, Anderson PL, Everson GT (2012) Review and management of drug interactions with boceprevir and telaprevir. Hepatology 55:1620–1628

    Article  PubMed  CAS  Google Scholar 

  8. Rajagopalan R, Misialek S, Stevens SK, Myszka DG, Brandhuber BJ, Ballard JA, Andrews SW, Seiwert SD, Kossen K (2009) Inhibition and binding kinetics of the hepatitis C virus NS3 protease inhibitor ITMN-191 reveals tight binding and slow dissociative behavior. Biochemistry 48(11):2559–2568

    Article  PubMed  CAS  Google Scholar 

  9. Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, Kossen K, Rajagopalan PT, Misialek S, Stevens SK, Stoycheva A, Hong J, Lim SR, Qin X, Rieger R, Condroski KR, Zhang H, Do MG, Lemieux C, Hingorani GP, Hartley DP, Josey JA, Pan L, Beigelman L, Blatt LM (2008) Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother 52(12):4432–4441

    Article  PubMed  CAS  Google Scholar 

  10. Everson G, Cooper C, Hezode C, Shiffman ML, Yoshida E, Beltran-Jaramillo T, Ferenci P, Zeuzem S, Brunda M, Shulman N, Navarro MT, Voulgari A, Le Pogam S, Najera I, Yetzer ES (2012) High SVR24 rates with ritonavir-boosted danoprevir plus Peg-IFNα-2a (40KD)/RBV in HCV genotype 1 or 4 patients in the DAUPHINE study. Hepatology 56(4 Suppl):552A

    Google Scholar 

  11. Abbott Laboratories (2011) Norvir Prescribing information. Abbott Laboratories, North Chicago. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020945s034lbl.pdf. Accessed 23 July 2012

  12. Foisy MM, Yakiwchuk EM, Hughes CA (2008) Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 42(7):1048–1059

    Article  PubMed  CAS  Google Scholar 

  13. Becker SL (2003) The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy. Expert Opin Investig Drugs 12(3):401–412

    Article  PubMed  CAS  Google Scholar 

  14. Scott JD (2005) Simplifying the treatment of HIV infection with ritonavir-boosted protease inhibitors in antiretroviral-experienced patients. Am J Health Syst Pharm 62:809–815

    PubMed  CAS  Google Scholar 

  15. Hill A, van der Lugt J, Sawyer W, Boffito M (2009) How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials. AIDS 23:2237–2245

    Article  PubMed  CAS  Google Scholar 

  16. Reddy MB, Chen Y, Haznedar JO, Fretland J, Blotner S, Smith P, Tran JQ (2012) Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study. Clin Pharmacokinet 51(7):457–465

    Article  PubMed  CAS  Google Scholar 

  17. Goezler P, Morcos PN, Tran J, Wen B, Shulman N, Smith P, Singer T, Brennan B, Hammond J (2012) Coadministration of ritonavir with the HCV protease inhibitor danoprevir substantially reduces reactive metabolite formation both in vitro and in vivo. Hepatology 56(4 Suppl):580A

    Google Scholar 

  18. Morcos PN, Brennan B, Blotner S, Naidu K, Fretland J, Tran JQ (2009) The effect of R7227 (ITMN-191), a novel hepatitis C virus (HCV) protease inhibitor on the pharmacokinetics (PK) of midazolam, a sensitive CYP3A4 probe substrate, in healthy volunteers. In: 4th Int Workshop on Clinical Pharmacology of Hepatitis Therapy. Abstract 8. Boston

  19. Zhou H, Tong Z, McLeod JF (2004) “Cocktail” approaches and strategies in drug development: valuable tool or flawed science? J Clin Pharmacol 44(2):120–134

    Article  PubMed  CAS  Google Scholar 

  20. Kuhlmann J, Mück W (2001) Clinical-pharmacological strategies to assess drug interaction potential during drug development. Drug Saf 24(10):715–725

    Article  PubMed  CAS  Google Scholar 

  21. Gane EJ, Rouzier R, Stedman C, Wiercinska-Drapalo A, Horban A, Chang L, Zhang Y, Sampeur P, Nájera I, Smith P, Shulman NS, Tran JQ (2011) Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients. J Hepatol 55(5):972–979

    Article  PubMed  CAS  Google Scholar 

  22. Gane EJ, Rouzier R, Wiercinska-Drapalo A, Larrey DG, Bhardwaj R, Brennan BJ, Giraudon M, Le Pogam S, Nájera I, Petric R, Tran JQ, Kulkarni R, Zhang Y, Smith P, Yetzer ES, Shulman NS (2012) Sustained virological response (SVR) rate of 67% in HCV genotype 1-infected prior null responders treated with danoprevir/ritonavir (DNVr) in combination with peginterferon alfa-2a (40KD) plus ribavirin (PegIFN α-2a/RBV). Hepatology 56(4 Suppl):558A

    Google Scholar 

  23. US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2012) Guidance for industry: drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM292362.pdf. Accessed 12 June 2012

  24. Bristol-Myers Squibb Co. (2011) Coumadin prescribing information. Bristol-Myers Squibb Co., Princeton. Available at: http://packageinserts.bms.com/pi/pi_coumadin.pdf. Accessed 23 July 2012

  25. Turpault S, Brian W, Van Horn R, Santoni A, Poitiers F, Donazzolo Y, Boulenc X (2009) Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol 68(6):928–935

    Article  PubMed  CAS  Google Scholar 

  26. Pentikäinen PJ, Välisalmi L, Himberg JJ, Crevoisier C (1989) Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 29(3):272–277

    Article  PubMed  Google Scholar 

  27. Guzmán-Fulgencio M, Jiménez JL, Berenguer J, Fernández-Rodríguez A, López JC, Cosín J, Miralles P, Micheloud D, Muñoz-Fernández MÁ, Resino S (2012) Plasma IL-6 and IL-9 predict the failure of interferon-α plus ribavirin therapy in HIV/HCV-coinfected patients. J Antimicrob Chemother 67(5):1238–1245

    Article  PubMed  Google Scholar 

  28. Ueyama M, Nakagawa M, Sakamoto N, Onozuka I, Funaoka Y, Watanabe T, Nitta S, Kiyohashi K, Kitazume A, Murakawa M, Nishimura-Sakurai Y, Sekine-Osajima Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M, Ochanomizu-Liver Conference Study Group (2011) Serum interleukin-6 levels correlate with resistance to treatment of chronic hepatitis C infection with pegylated-interferon-α2b plus ribavirin. Antivir Ther 16:1081–1091

    Article  PubMed  CAS  Google Scholar 

  29. Dickmann LJ, Patel SK, Rock DA, Wienkers LC, Slatter JG (2011) Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos 39:1415–1422

    Article  PubMed  CAS  Google Scholar 

  30. Aitken AE, Morgan ET (2007) Gene-specific effects of inflammatory cytokines on cytochrome P4502C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab Dispos 35(9):1687–1693

    Article  PubMed  CAS  Google Scholar 

  31. Dumond JB, Vourvahis M, Rezk NL, Patterson KB, Tien HC, White N, Jennings SH, Choi SO, Li J, Wagner MJ, La-Beck NM, Drulak M, Sabo JP, Castles MA, Macgregor TR, Kashuba AD (2010) A phenotype-genotype approach to predicting CYP450 and P-glycoprotein drug interactions with the mixed inhibitor/inducer tipranavir/ritonavir. Clin Pharmacol Ther 87(6):735–742

    Article  PubMed  CAS  Google Scholar 

  32. Genentech Inc (2012) Invirase prescribing information Genentech Inc., South San Francisco. Available at: http://www.gene.com/gene/products/information/invirase/pdf/pi.pdf. Accessed 23 July 2012

  33. Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ Jr, Klein CE, Rublein JC, Kashuba AD (2006) Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquir Immune Def Syndr 42(1):52–60

    CAS  Google Scholar 

  34. Liptrott NJ, Owen A (2011) The role of cytokines in the regulation of drug disposition: extended functional pleiotropism? Expert Opin Drug Metab Toxicol 7(3):341–352

    Article  PubMed  CAS  Google Scholar 

  35. Ingelman-Sundberg M (2004) Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms. Naunyn Schmiedeberg’s Arch Pharmacol 369(1):89–104

    Article  CAS  Google Scholar 

  36. Tomalik-Scharte D, Lazar A, Fuhr U, Kirchheiner J (2008) The clinical role of genetic polymorphisms in drug-metabolizing enzymes. Pharmacogenomics J 8:4–15

    Article  PubMed  CAS  Google Scholar 

  37. Shirasaka Y, Chang S-Y, Grubb MF, Peng C-C, Thummel KE, Isoherranen N, Rodrigues AD (2013) Impact of CYP3A5 expression on the inhibition of CYP3A-catalyzed drug metabolism: considerations for modelling CYP3A-mediated drug-drug interactions. Drug Metabol Dispos. doi:10.1124/dmd.112.049940

    Google Scholar 

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Acknowledgements

We would like to thank the patients, their families, the nurses, and the investigators who participated in this study. This work was supported by F. Hoffmann-La Roche Ltd..

Declaration of interest

This work was supported by F. Hoffmann-La Roche Ltd.. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. PNM, MG, NS, BJB are current employees at Roche/Genentech. LC, RK, JQT and PFS were employees at Hoffmann-La Roche Inc at the time of the study.

Author information

Author notes

  1. Linda Chang

    Present address: MedImmune LLC, Hayward, CA, USA

  2. Patrick F. Smith

    Present address: d3 Limited, Montville, NJ, USA

  3. Jonathan Q. Tran

    Present address: Biogen Idec, Cambridge, MA, USA

Authors and Affiliations

  1. Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ, 07110, USA

    Peter N. Morcos, Barbara J. Brennan & Patrick F. Smith

  2. Hoffmann-La Roche Inc., Palo Alto, CA, USA

    Linda Chang & Jonathan Q. Tran

  3. Guardian Analytics, Mountain View, CA, USA

    Rohit Kulkarni

  4. F. Hoffmann-La Roche Ltd, Basel, Switzerland

    Mylene Giraudon

  5. Genentech, South San Francisco, CA, USA

    Nancy Shulman

  6. University at Buffalo School of Pharmacy, Buffalo, NY, USA

    Patrick F. Smith

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Corresponding author

Correspondence to Peter N. Morcos.

Additional information

Disclosure of prior publication

L. Chang, Y. Zhang, P. Weigl, N. Shulman, P. Smith, J Tran: Danoprevir does not change the effects of ritonavir on the pharmacokinetics of cytochrome P450 3A substrate midazolam and C29 substrate warfarin. Presented at the 112th Annual Meeting of the American Society Clinical Pharmacology Therapeutics (ASCPT), Dallas, Texas, March 2–5, 2011. Poster PIII-77

This study is registered on ClinicalTrials.gov (NCT01185860)

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Morcos, P.N., Chang, L., Kulkarni, R. et al. A randomised study of the effect of danoprevir/ritonavir or ritonavir on substrates of cytochrome P450 (CYP) 3A and 2C9 in chronic hepatitis C patients using a drug cocktail. Eur J Clin Pharmacol 69, 1939–1949 (2013). https://doi.org/10.1007/s00228-013-1556-y

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  • DOI: https://doi.org/10.1007/s00228-013-1556-y

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