Development of a Physiologically Based Pharmacokinetic Model to Predict Disease-Mediated Therapeutic Protein–Drug Interactions: Modulation of Multiple Cytochrome P450 Enzymes by Interleukin-6
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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.
KEY WORDScytochrome P450 interleukin-6 monoclonal antibody sirukumab therapeutic protein–drug interaction
- 9.Actemra (package insert). South San Francisco CG, Inc; 2014.Google Scholar
- 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
- 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.
- 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
- 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
- 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
- 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
- 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
- 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