Abstract
Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.
Similar content being viewed by others
Abbreviations
- CYP:
-
Cytochrome P450
- Disease-DDI:
-
Disease-drug-drug interactions
- IL:
-
Interleukin
- TNFα:
-
Tumor necrosis factor α
References
Christophers E. Psoriasis–epidemiology and clinical spectrum. Clin Exp Dermatol. 2001;26(4):314–20.
Sivamani RK, Goodarzi H, Garcia MS, Raychaudhuri SP, Wehrli LN, Ono Y, et al. Biologic Therapies in the Treatment of Psoriasis: A Comprehensive Evidence-Based Basic Science and Clinical Review and a Practical Guide to Tuberculosis Monitoring. Clin Rev Allergy Immunol 2012 Feb 5.
Perera GK, Di MP, Nestle FO. Psoriasis. Annu Rev Pathol. 2012;7:385–422.
Nijsten T, Margolis DJ, Feldman SR, Rolstad T, Stern RS. Traditional systemic treatments have not fully met the needs of psoriasis patients: Results from a national survey. J Am Acad Dermatol. 2005;52(3 Pt 1):434–44.
Kupetsky EA, Mathers AR, Ferris LK. Anti-cytokine therapy in the treatment of psoriasis. Cytokine. 2013;61(3):704–12.
Ryan C, Abramson A, Patel M, Menter A. Current investigational drugs in psoriasis. Expert Opin Investig Drugs. 2012;21(4):473–87.
Lew W, Bowcock AM, Krueger JG. Psoriasis vulgaris: cutaneous lymphoid tissue supports T-cell activation and “Type 1” inflammatory gene expression. Trends Immunol. 2004;25(6):295–305.
Sivamani RK, Correa G, Ono Y, Bowen MP, Raychaudhuri SP, Maverakis E. Biological therapy of psoriasis. Indian J Dermatol. 2010;55(2):161–70.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009;361(5):496–509.
Nograles KE, Krueger JG. Anti-cytokine therapies for psoriasis. Exp Cell Res. 2011;317(9):1293–300.
Pietrzak AT, Zalewska A, Chodorowska G, Krasowska D, Michalak-Stoma A, Nockowski P, et al. Cytokines and anticytokines in psoriasis. Clin Chim Acta. 2008;394(1–2):7–21.
Asadullah K, Docke WD, Ebeling M, Friedrich M, Belbe G, Audring H, et al. Interleukin 10 treatment of psoriasis: clinical results of a phase 2 trial. Arch Dermatol. 1999;135(2):187–92.
Salim A, Emerson R. Targeting interleukin-2 as a treatment for psoriasis. Curr Opin Investig Drugs. 2001;2(11):1546–8.
Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648–51.
Tohyama M, Yang L, Hanakawa Y, Dai X, Shirakata Y, Sayama K. IFN-alpha enhances IL-22 receptor expression in keratinocytes: a possible role in the development of psoriasis. J Invest Dermatol. 2012;132(7):1933–5.
Huang SM, Zhao H, Lee JI, Reynolds K, Zhang L, Temple R, et al. Therapeutic protein-drug interactions and implications for drug development. Clin Pharmacol Ther. 2010;87(4):497–503.
Morgan ET. Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther. 2009;85(4):434–8.
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.
Garcia-Valladares I, Cuchacovich R, Espinoza LR. Comparative assessment of biologics in treatment of psoriasis: Drug design and clinical effectiveness of ustekinumab. Drug Des Devel Ther. 2011;5:41–9.
Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, Wang Y, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet. 2008;371(9625):1665–74.
Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, Yeilding N, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet. 2008;371(9625):1675–84.
Di MP, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep 2010;2.
Tonel G, Conrad C, Laggner U, Di MP, Grys K, McClanahan TK, et al. Cutting edge: a critical functional role for IL-23 in psoriasis. J Immunol. 2010;185(10):5688–91.
Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52):52ra72.
Papp KA, Reid C, Foley P, Sinclair R, Salinger DH, Williams G, et al. Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial. J Invest Dermatol 2012 May 24.
Martin DA, Towne JE, Kricorian G, Klekotka P, Gudjonsson JE, Krueger JG, et al. The Emerging Role of IL-17 in the Pathogenesis of Psoriasis: Preclinical and Clinical Findings. J Invest Dermatol 2012 Jun 7.
Weger W. Current status and new developments in the treatment of psoriasis and psoriatic arthritis with biological agents. Br J Pharmacol. 2010;160(4):810–20.
Al-Hoqail IA. Personalized medicine in psoriasis: Concept and applications. Curr Vasc Pharmacol. 2010;8(3):432–6.
de Vlam K, Gottlieb AB, Fitzgerald O. Biological biomarkers in psoriatic disease. A review. J Rheumatol. 2008;35(7):1443–8.
Enerback C. Soluble biomarkers in psoriasis. Eur J Dermatol. 2011;21(6):844–50.
Flisiak I, Zaniewski P, Chodynicka B. Plasma TGF-beta1, TIMP-1, MMP-1 and IL-18 as a combined biomarker of psoriasis activity. Biomarkers. 2008;13(5):549–56.
Prieto-Perez R, Cabaleiro T, Dauden E, Abad-Santos F. Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases. Pharmacogenomics J. 2013;13(4):297–305.
Rashmi R, Rao KS, Basavaraj KH. A comprehensive review of biomarkers in psoriasis. Clin Exp Dermatol. 2009;34(6):658–63.
Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab pegol for the treatment of Crohn's disease. N Engl J Med. 2007;357(3):228–38.
Pappas DA, Bathon JM, Hanicq D, Yasothan U, Kirkpatrick P. Golimumab. Nat Rev Drug Discov. 2009;8(9):695–6.
Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117(2):244–79.
Reich K, Ortonne JP, Gottlieb AB, Terpstra IJ, Coteur G, Tasset C, et al. Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: Results of a phase II randomized, placebo-controlled trial with a re-treatment extension. Br J Dermatol. 2012;167(1):180–90.
Horiuchi T, Mitoma H, Harashima S, Tsukamoto H, Shimoda T. Transmembrane TNF-alpha: Structure, function and interaction with anti-TNF agents. Rheumatology (Oxford). 2010;49(7):1215–28.
Schottelius AJ, Moldawer LL, Dinarello CA, Asadullah K, Sterry W, Edwards III CK. Biology of tumor necrosis factor-alpha-implications for psoriasis. Exp Dermatol. 2004;13(4):193–222.
Mussi A, Bonifati C, Carducci M, D'Agosto G, Pimpinelli F, D'Urso D, et al. Serum TNF-alpha levels correlate with disease severity and are reduced by effective therapy in plaque-type psoriasis. J Biol Regul Homeost Agents. 1997;11(3):115–8.
Soegaard-Madsen L, Johansen C, Iversen L, Kragballe K. Adalimumab therapy rapidly inhibits p38 mitogen-activated protein kinase activity in lesional psoriatic skin preceding clinical improvement. Br J Dermatol. 2010;162(6):1216–23.
Caproni M, Antiga E, Melani L, Volpi W, Del BE, Fabbri P. Serum levels of IL-17 and IL-22 are reduced by etanercept, but not by acitretin, in patients with psoriasis: a randomized-controlled trial. J Clin Immunol. 2009;29(2):210–4.
Reddy M, Davis C, Wong J, Marsters P, Pendley C, Prabhakar U. Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275. Cell Immunol. 2007;247(1):1–11.
Gottlieb AB, Goldminz AM. Ustekinumab for psoriasis and psoriatic arthritis. J Rheumatol Suppl 2012 Jul;89:86-9.
Traczewski P, Rudnicka L. Briakinumab for the treatment of plaque psoriasis. BioDrugs. 2012;26(1):9–20.
Lowes MA, Russell CB, Martin DA, Towne JE, Krueger JG. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses. Trends Immunol. 2013;34(4):174–81.
Di MP, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep 2010;2.
Papp KA, Reid C, Foley P, Sinclair R, Salinger DH, Williams G, et al. Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial. J Invest Dermatol 2012 May 24.
Leonardi C, Matheson R, Zachariae C, Cameron G, Li L, Edson-Heredia E, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med. 2012;366(13):1190–9.
Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I, Bruin G, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med. 2010;2(52):52ra72.
Papp KA, Leonardi C, Menter A, Ortonne JP, Krueger JG, Kricorian G, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13):1181–9.
Waisman A. To be 17 again–anti-interleukin-17 treatment for psoriasis. N Engl J Med. 2012;366(13):1251–2.
Gandhi M, Alwawi E, Gordon KB. Anti-p40 antibodies ustekinumab and briakinumab: Blockade of interleukin-12 and interleukin-23 in the treatment of psoriasis. Semin Cutan Med Surg. 2010;29(1):48–52.
Di CA, Di MP, Nestle FO. The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol. 2009;129(6):1339–50.
Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol. 2007;8(9):950–7.
van Beelen AJ, Teunissen MB, Kapsenberg ML, de Jong EC. Interleukin-17 in inflammatory skin disorders. Curr Opin Allergy Clin Immunol. 2007;7(5):374–81.
Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199(1):125–30.
Shaker OG, Moustafa W, Essmat S, Abdel-Halim M, El-Komy M. The role of interleukin-12 in the pathogenesis of psoriasis. Clin Biochem. 2006;39(2):119–25.
Krueger GG. Selective targeting of T cell subsets: focus on alefacept—a remittive therapy for psoriasis. Expert Opin Biol Ther. 2002;2(4):431–41.
Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med. 2003;349(21):2004–13.
Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol. 2006;46:123–49.
Zaba LC, Suarez-Farinas M, Fuentes-Duculan J, Nograles KE, Guttman-Yassky E, Cardinale I, et al. Effective treatment of psoriasis with etanercept is linked to suppression of IL-17 signaling, not immediate response TNF genes. J Allergy Clin Immunol. 2009;124(5):1022–10.
Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suarez-Farinas M, Fuentes-Duculan J, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med. 2007;204(13):3183–94.
Reddy M, Torres G, McCormick T, Marano C, Cooper K, Yeilding N, et al. Positive treatment effects of ustekinumab in psoriasis: analysis of lesional and systemic parameters. J Dermatol. 2010;37(5):413–25.
Jacobson TA. Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors. Am J Cardiol. 2004;94(9):1140–6.
Kyrklund C, Backman JT, Kivisto KT, Neuvonen M, Laitila J, Neuvonen PJ. Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther. 2000;68(6):592–7.
Gupta R, Levin E, Wu JJ, Koo J, Liao W. An update on drug-drug interactions with biologics for the treatment of moderate-to-severe psoriasis. J Dermatolog Treat 2013 Aug 27.
Grossman RM, Krueger J, Yourish D, Granelli-Piperno A, Murphy DP, May LT, et al. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A. 1989;86(16):6367–71.
Elango T, Dayalan H, Subramanian S, Gnanaraj P, Malligarjunan H. Serum interleukin-6 levels in response to methotrexate treatment in psoriatic patients. Clin Chim Acta. 2012;413(19–20):1652–6.
Galadari I, Sheriff MO. Estimation of interleukin-6 level in psoriasis patients. Eur Ann Allergy Clin Immunol. 2005;37(2):63–5.
Bevelacqua V, Libra M, Mazzarino MC, Gangemi P, Nicotra G, Curatolo S, et al. Long pentraxin 3: a marker of inflammation in untreated psoriatic patients. Int J Mol Med. 2006;18(3):415–23.
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.
Drug interaction studies -- study design,data analysis,implications for dosing,and labeling recommendations. FDA Guidance for Industry (Draft) 2012 Feb.
Sinz M, Wallace G, Sahi J. Current industrial practices in assessing CYP450 enzyme induction: preclinical and clinical. AAPS J. 2008;10(2):391–400.
Johnson-Huang LM, Pensabene CA, Shah KR, Pierson KC, Kikuchi T, Lentini T, et al. Post-therapeutic relapse of psoriasis after CD11a blockade is associated with T cells and inflammatory myeloid DCs. PLoS ONE. 2012;7(2):e30308.
Carey W, Glazer S, Gottlieb AB, Lebwohl M, Leonardi C, Menter A, et al. Relapse, rebound, and psoriasis adverse events: an advisory group report. J Am Acad Dermatol. 2006;54(4 Suppl 1):S171–81.
Leonardi C, Langley RG, Papp K, Tyring SK, Wasel N, Vender R, et al. Adalimumab for treatment of moderate to severe chronic plaque psoriasis of the hands and feet: efficacy and safety results from REACH, a randomized, placebo-controlled, double-blind trial. Arch Dermatol. 2011;147(4):429–36.
Kaur S, Zilmer K, Kairane C, Kals M, Zilmer M. Clear differences in adiponectin level and glutathione redox status revealed in obese and normal-weight patients with psoriasis. Br J Dermatol. 2008;159(6):1364–7.
Vasilopoulos Y, Sourli F, Zafiriou E, Klimi E, Ioannou M, Mamuris Z, et al. High serum levels of HIF-1alpha in psoriatic patients correlate with an over-expression of IL-6. Cytokine. 2013;62(1):38–9.
Takahashi H, Tsuji H, Hashimoto Y, Ishida-Yamamoto A, Iizuka H. Serum cytokines and growth factor levels in Japanese patients with psoriasis. Clin Exp Dermatol. 2010;35(6):645–9.
Nakajima H, Nakajima K, Tarutani M, Morishige R, Sano S. Kinetics of circulating Th17 cytokines and adipokines in psoriasis patients. Arch Dermatol Res. 2011;303(6):451–5.
Zalewska A, Glowacka E, Wyczolkowska J, Tchorzewski H, Narbutt J, Sysa-Jedrzejowska A. Interleukin 6 and 8 levels in plasma and fibroblast cultures in psoriasis. Mediat Inflamm. 2006;2006(1):81767.
Szepietowski JC, Bielicka E, Nockowski P, Noworolska A, Wasik F. Increased interleukin-7 levels in the sera of psoriatic patients: Lack of correlations with interleukin-6 levels and disease intensity. Clin Exp Dermatol. 2000;25(8):643–7.
Anderson KS, Petersson S, Wong J, Shubbar E, Lokko NN, Carlstrom M, et al. Elevation of serum epidermal growth factor and interleukin 1 receptor antagonist in active psoriasis vulgaris. Br J Dermatol. 2010;163(5):1085–9.
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;2005(5):273–9.
Acknowledgments
The authors wish to thank Dr. E. Dennis Bashaw for his critical review of this manuscript and valuable comments.
Author information
Authors and Affiliations
Corresponding author
Additional information
The opinions expressed in this article are those of the authors who are affiliated with the United States Food and Drug Administration (FDA) and do not necessarily reflect the official views or policies of the FDA. The authors did not receive external funding for this project.
Rights and permissions
About this article
Cite this article
Wang, J., Wang, YM.C. & Ahn, HY. Biological Products for the Treatment of Psoriasis: Therapeutic Targets, Pharmacodynamics and Disease-Drug-Drug Interaction Implications. AAPS J 16, 938–947 (2014). https://doi.org/10.1208/s12248-014-9637-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1208/s12248-014-9637-0