The AAPS Journal

, Volume 18, Issue 3, pp 767–776 | Cite as

Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6

  • Xiling Jiang
  • Yanli Zhuang
  • Zhenhua Xu
  • Weirong Wang
  • Honghui Zhou
Research Article


Disease-mediated therapeutic protein–drug interactions have recently gained attention from regulatory agencies and pharmaceutical industries in the development of new biological products. In this study, we developed a physiologically based pharmacokinetic (PBPK) model using SimCYP to predict the impact of elevated interleukin-6 (IL-6) levels on cytochrome P450 (CYP) enzymes and the treatment effect of an anti-IL-6 monoclonal antibody, sirukumab, in patients with rheumatoid arthritis (RA). A virtual RA patient population was first constructed by incorporating the impact of systemic IL-6 level on hepatic and intestinal expression of multiple CYP enzymes with information from in vitro studies. Then, a PBPK model for CYP enzyme substrates was developed for healthy adult subjects. After incorporating the virtual RA patient population, the PBPK model was applied to quantitatively predict pharmacokinetics of multiple CYP substrates in RA patients before and after sirukumab treatment from a clinical cocktail drug interaction study. The results suggested that, compared with observed clinical data, changes in systemic exposure to multiple CYP substrates by anti-IL-6 treatment in virtual RA patients have been reasonably captured by the PBPK model, as manifested by modulations in area under plasma concentration versus time curves for midazolam, omeprazole, S-warfarin, and caffeine. This PBPK model reasonably captured the modulation effect of IL-6 and sirukumab on activity of CYP3A, CYP2C9, CYP2C19, and CYP1A2 and holds the potential to be utilized to assess the modulation effect of sirukumab on the metabolism and pharmacokinetics of concomitant small-molecule drugs in RA patients.


cytochrome P450 interleukin-6 monoclonal antibody sirukumab therapeutic protein–drug interaction 



This study was supported by Janssen Research & Development, LLC. The authors thank Robert Achenbach of Janssen Scientific Affairs, LLC, for the manuscript preparation and submission support.


Conflict of Interest

The authors Jiang, Zhuang, Xu, Wang, and Zhou are employees of Janssen Research & Development, LLC, at the time of the study. All authors own stock in Johnson & Johnson.


  1. 1.
    Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85(4):434–8. doi: 10.1038/clpt.2008.302.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Dowlatshahi EA, van der Voort EA, Arends LR, Nijsten T. Markers of systemic inflammation in psoriasis: a systematic review and meta-analysis. Br J Dermatol. 2013;169(2):266–82. doi: 10.1111/bjd.12355.CrossRefPubMedGoogle Scholar
  3. 3.
    Kishimoto T. IL-6: from its discovery to clinical applications. Int Immunol. 2010;22(5):347–52. doi: 10.1093/intimm/dxq030.CrossRefPubMedGoogle Scholar
  4. 4.
    Gao SP, Mark KG, Leslie K, Pao W, Motoi N, Gerald WL, et al. Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas. J Clin Invest. 2007;117(12):3846–56. doi: 10.1172/JCI31871.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Dickmann LJ, Patel SK, Rock DA, Wienkers LC, Slatter JG. Effects of interleukin-6 (IL-6) and an anti-IL-6 monoclonal antibody on drug-metabolizing enzymes in human hepatocyte culture. Drug Metab Dispos. 2011;39(8):1415–22. doi: 10.1124/dmd.111.038679.CrossRefPubMedGoogle Scholar
  6. 6.
    Dallas S, Sensenhauser C, Batheja A, Singer M, Markowska M, Zakszewski C, et al. De-risking bio-therapeutics for possible drug interactions using cryopreserved human hepatocytes. Curr Drug Metab. 2012;13(7):923–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Dickmann LJ, Patel SK, Wienkers LC, Slatter JG. Effects of interleukin 1beta (IL-1beta) and IL-1beta/interleukin 6 (IL-6) combinations on drug metabolizing enzymes in human hepatocyte culture. Curr Drug Metab. 2012;13(7):930–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Schmitt C, Kuhn B, Zhang X, Kivitz AJ, Grange S. Disease-drug-drug interaction involving tocilizumab and simvastatin in patients with rheumatoid arthritis. Clin Pharmacol Ther. 2011;89(5):735–40. doi: 10.1038/clpt.2011.35.CrossRefPubMedGoogle Scholar
  9. 9.
    Actemra (package insert). South San Francisco CG, Inc; 2014.Google Scholar
  10. 10.
    Zhuang Y, de Vries DE, Xu Z, Marciniak SJ, Chen D, Leon F, et al. Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-lnterleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase I study in patients with rheumatoid arthritis using a cocktail approach. J Clin Pharmacol. 2015. doi: 10.1002/jcph.561.PubMedGoogle Scholar
  11. 11.
    Huang SM, Rowland M. The role of physiologically based pharmacokinetic modeling in regulatory review. Clin Pharmacol Ther. 2012;91(3):542–9. doi: 10.1038/clpt.2011.320.CrossRefPubMedGoogle Scholar
  12. 12.
    Rowland M, Peck C, Tucker G. Physiologically-based pharmacokinetics in drug development and regulatory science. Annu Rev Pharmacol Toxicol. 2011;51:45–73. doi: 10.1146/annurev-pharmtox-010510-100540.CrossRefPubMedGoogle Scholar
  13. 13.
    Machavaram KK, Almond LM, Rostami-Hodjegan A, Gardner I, Jamei M, Tay S, et al. A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: suppression of CYP3A by IL-6. Clin Pharmacol Ther. 2013;94(2):260–8. doi: 10.1038/clpt.2013.79.CrossRefPubMedGoogle Scholar
  14. 14.
    Ogata A, Tanimura K, Sugimoto T, Inoue H, Urata Y, Matsubara T, et al. Phase III study of the efficacy and safety of subcutaneous versus intravenous tocilizumab monotherapy in patients with rheumatoid arthritis. Arthritis Care Res. 2014;66(3):344–54. doi: 10.1002/acr.22110.CrossRefGoogle Scholar
  15. 15.
    Perry MG, Kirwan JR, Jessop DS, Hunt LP. Overnight variations in cortisol, interleukin 6, tumour necrosis factor alpha and other cytokines in people with rheumatoid arthritis. Ann Rheum Dis. 2009;68(1):63–8. doi: 10.1136/ard.2007.086561.
  16. 16.
    Chung SJ, Kwon YJ, Park MC, Park YB, Lee SK. The correlation between increased serum concentrations of interleukin-6 family cytokines and disease activity in rheumatoid arthritis patients. Yonsei Med J. 2011;52(1):113–20. doi: 10.3349/ymj.2011.52.1.113.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Crofford LJ, Kalogeras KT, Mastorakos G, Magiakou MA, Wells J, Kanik KS, et al. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab. 1997;82(4):1279–83. doi: 10.1210/jcem.82.4.3852.CrossRefPubMedGoogle Scholar
  18. 18.
    Dasgupta B, Corkill M, Kirkham B, Gibson T, Panayi G. Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. J Rheumatol. 1992;19(1):22–5.PubMedGoogle Scholar
  19. 19.
    Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, et al. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol. 1988;18(11):1797–801. doi: 10.1002/eji.1830181122.CrossRefPubMedGoogle Scholar
  20. 20.
    Knudsen LS, Christensen IJ, Lottenburger T, Svendsen MN, Nielsen HJ, Nielsen L, et al. Pre-analytical and biological variability in circulating interleukin 6 in healthy subjects and patients with rheumatoid arthritis. Biomarkers. 2008;13(1):59–78. doi: 10.1080/13547500701615017.CrossRefPubMedGoogle Scholar
  21. 21.
    Sakamoto K, Arakawa H, Mita S, Ishiko T, Ikei S, Egami H, et al. Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine. 1994;6(2):181–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani A, et al. Raised interleukin-6 levels in obese patients. Obes Res. 2000;8(9):673–5. doi: 10.1038/oby.2000.86.CrossRefPubMedGoogle Scholar
  23. 23.
    Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12, IL-17, and IL-18 in patients with active psoriasis and correlation with disease severity. Mediat Inflamm. 2005;5:273–9. doi: 10.1155/MI.2005.273.CrossRefGoogle Scholar
  24. 24.
    Ataseven H, Bahcecioglu IH, Kuzu N, Yalniz M, Celebi S, Erensoy A, et al. The levels of ghrelin, leptin, TNF-alpha, and IL-6 in liver cirrhosis and hepatocellular carcinoma due to HBV and HDV infection. Mediat Inflamm. 2006;2006(4), 78380. doi: 10.1155/MI/2006/78380.Google Scholar
  25. 25.
    Wang H, Moser M, Schiltenwolf M, Buchner M. Circulating cytokine levels compared to pain in patients with fibromyalgia—a prospective longitudinal study over 6 months. J Rheumatol. 2008;35(7):1366–70.PubMedGoogle Scholar
  26. 26.
    Haas CE, Kaufman DC, Jones CE, Burstein AH, Reiss W. Cytochrome P450 3A4 activity after surgical stress. Crit Care Med. 2003;31(5):1338–46. doi: 10.1097/01.CCM.0000063040.24541.49.CrossRefPubMedGoogle Scholar
  27. 27.
    Jamei M, Marciniak S, Feng K, Barnett A, Tucker G, Rostami-Hodjegan A. The Simcyp population-based ADME simulator. Expert Opin Drug Metab Toxicol. 2009;5(2):211–23. doi: 10.1517/17425250802691074.CrossRefPubMedGoogle Scholar
  28. 28.
    Rowland Yeo K, Jamei M, Yang J, Tucker GT, Rostami-Hodjegan A. Physiologically based mechanistic modelling to predict complex drug-drug interactions involving simultaneous competitive and time-dependent enzyme inhibition by parent compound and its metabolite in both liver and gut—the effect of diltiazem on the time-course of exposure to triazolam. Eur J Pharm Sci. 2010;39(5):298–309. doi: 10.1016/j.ejps.2009.12.002.CrossRefPubMedGoogle Scholar
  29. 29.
    Sanada H, Sekimoto M, Kamoshita A, Degawa M. Changes in expression of hepatic cytochrome P450 subfamily enzymes during development of adjuvant-induced arthritis in rats. J Toxicol Sci. 2011;36(2):181–90.CrossRefPubMedGoogle Scholar
  30. 30.
    Uno S, Kawase A, Tsuji A, Tanino T, Iwaki M. Decreased intestinal CYP3A and P-glycoprotein activities in rats with adjuvant arthritis. Drug Metab Pharmacokinet. 2007;22(4):313–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Evers R, Dallas S, Dickmann LJ, Fahmi OA, Kenny JR, Kraynov E, et al. Critical review of preclinical approaches to investigate cytochrome p450-mediated therapeutic protein drug-drug interactions and recommendations for best practices: a white paper. Drug Metab Dispos. 2013;41(9):1598–609. doi: 10.1124/dmd.113.052225.CrossRefPubMedGoogle Scholar
  32. 32.
    Gardner D, Lacy E, Wu S, Shealy D. Preclinical characterization of sirukumab, a human monoclonal antibody that targets human interleukin-6 signaling. Ann Rheum Dis. 2015;74:207. doi: 10.1136/annrheumdis-2015-eular.5124.CrossRefGoogle Scholar
  33. 33.
    Zhuang Y, Xu Z, de Vries DE, Wang Q, Shishido A, Comisar C, et al. Pharmacokinetics and safety of sirukumab following a single subcutaneous administration to healthy Japanese and Caucasian subjects. Int J Clin Pharmacol Ther. 2013;51(3):187–99. doi: 10.5414/CP201785.CrossRefPubMedGoogle Scholar
  34. 34.
    Xu Z, Bouman-Thio E, Comisar C, Frederick B, Van Hartingsveldt B, Marini JC, et al. Pharmacokinetics, pharmacodynamics and safety of a human anti-IL-6 monoclonal antibody (sirukumab) in healthy subjects in a first-in-human study. Br J Clin Pharmacol. 2011;72(2):270–81. doi: 10.1111/j.1365-2125.2011.03964.x.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Chai X, Zeng S, Xie W. Nuclear receptors PXR and CAR: implications for drug metabolism regulation, pharmacogenomics and beyond. Expert Opin Drug Metab Toxicol. 2013;9(3):253–66. doi: 10.1517/17425255.2013.754010.CrossRefPubMedGoogle Scholar
  36. 36.
    Zhou SF, Wang B, Yang LP, Liu JP. Structure, function, regulation and polymorphism and the clinical significance of human cytochrome P450 1A2. Drug Metab Rev. 2010;42(2):268–354. doi: 10.3109/03602530903286476.CrossRefPubMedGoogle Scholar
  37. 37.
    Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci U S A. 2008;105(28):9721–6. doi: 10.1073/pnas.0804231105.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Jiang XL, Zhao P, Barrett JS, Lesko LJ, Schmidt S. Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children. CPT Pharmacometrics Syst Pharmacol. 2013;2, e80. doi: 10.1038/psp.2013.55.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Hsu V, de LT Vieira M, Zhao P, Zhang L, Zheng JH, Nordmark A, et al. Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations. Clin Pharmacokinet. 2014;53(3):283–93. doi: 10.1007/s40262-013-0117-y.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2016

Authors and Affiliations

  • Xiling Jiang
    • 1
  • Yanli Zhuang
    • 1
  • Zhenhua Xu
    • 1
  • Weirong Wang
    • 1
  • Honghui Zhou
    • 1
  1. 1.Biologics Clinical PharmacologyJanssen Research & Development, LLCSpring HouseUSA

Personalised recommendations