Advertisement

The AAPS Journal

, 20:76 | Cite as

Dashboards for Therapeutic Monoclonal Antibodies: Learning and Confirming

  • Diane R. Mould
  • Richard N. Upton
  • Jessica Wojciechowski
  • Becky L. Phan
  • Stacy Tse
  • Marla C. Dubinsky
Research Article Theme: Precision Medicine: Implications for the Pharmaceutical Sciences
  • 202 Downloads
Part of the following topical collections:
  1. Theme: Precision Medicine: Implications for the Pharmaceutical Sciences

Abstract

Inflammatory diseases (ID) are incurable, progressive diseases. Literature evidence cites increasing incidence of these diseases worldwide. When treatments with chemical immunosuppressive agents fail, patients are often treated with monoclonal antibodies (MAbs). However, MAb failure rates are generally high, with approximately half the patients being discontinued within 4 years, necessitating switching to another MAb. One potential cause of treatment failure is subtherapeutic exposure. Several studies demonstrated associations between trough MAb concentrations and clinical response, supporting the notion that improving drug exposure may result in improved outcomes. MAbs exhibit complex and highly variable pharmacokinetics in ID patients with numerous factors affecting clearance. Bayesian-guided dosing with dashboard systems is a new tool being investigated in the treatment of ID to reduce variability in exposure. Simulations suggest dashboards will be effective at maintaining patients at target troughs. However, when patients are dosed using doses or intervals outside those listed in prescribing information, there is concern that patients may have drug exposures beyond or below the ranges found to be safe and efficacious. This manuscript reviews the rationale behind dashboard development, evaluations of expected performance, and a simulated assessment of MAb exposure with dashboard-based dosing versus dosing based on the prescribing information. We introduce the concept of pharmacologic equivalence—if patients are dosed based on individual pharmacokinetics, the resulting exposure is consistent with exposures achieved using labeled dosing. We further show that dashboard-based dosing results in observed exposures that are generally contained within the range of exposures achieved with labeled dosing.

KEY WORDS

Bayes dashboard IBD individualized dosing monoclonal antibodies 

Notes

Compliance with Ethical Standards

Conflict of Interest

DR Mould is the founder and president of Projections Research Inc., a consulting company that conducts population PK and PKPD evaluations for the pharmaceutical industry. She is also a founder and member of Baysient LLC, a company specializing in dashboard systems. RN Upton is a consultant who works with Projections Research Inc. J Wojciechowski is a postdoctoral research fellow at Pfizer, Inc., USA. BL Phan and S Tse have no conflicts to disclose. MC Dubinsky has consulted for numerous pharmaceutical companies and received speaker fees.

References

  1. 1.
    Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369(9573):1627–40.CrossRefPubMedGoogle Scholar
  2. 2.
    Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142(1):46–54.CrossRefPubMedGoogle Scholar
  3. 3.
    Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955–2007. Arthritis Rheum 2010;62(6):1576–1582.Google Scholar
  4. 4.
    Wilson FC, Icen M, Crowson CS, McEvoy MT, Gabriel SE, Kremers HM. Time trends in epidemiology and characteristics of psoriatic arthritis over 3 decades: a population-based study. J Rheumatol. 2009;36(2):361–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Icen M, Crowson CS, McEvoy MT, Dann FJ, Gabriel SE, Maradit Kremers H. Trends in incidence of adult-onset psoriasis over three decades: a population-based study. J Am Acad Dermatol. 2009;60(3):394–401.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Travis SP, Stange EF, Lémann M, Oresland T, Chowers Y, Forbes A, D'Haens G, Kitis G, Cortot A, Prantera C, Marteau P, Colombel JF, Gionchetti P, Bouhnik Y, Tiret E, Kroesen J, Starlinger M, Mortensen NJ; European Crohn’s and Colitis Organisation. European evidence based consensus on the diagnosis and management of Crohn's disease: current management. Gut 2006; 55 Suppl 1: i16–i35.Google Scholar
  7. 7.
    Souto A, Maneiro JR, Gómez-Reino JJ. Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology (Oxford). 2016;55(3):523–34.Google Scholar
  8. 8.
    Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol. 2008;6(6):644–53.CrossRefPubMedGoogle Scholar
  9. 9.
    Gisbert JP, Panes J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Mould DR. The pharmacokinetics of biologics: a primer. Dig Dis. 2015;33(Suppl 1):61–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Kennedy DM, Skillen AW, Self CH. Glycation increases the vascular clearance rate of IgG in mice. Clin Exp Immunol. 1993;94(3):447–51.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Brown P, Clark T, Dowson G, Warren L, Hamlin J, Hull M, et al. Relationship of body mass index to clinical outcomes after infliximab therapy in patients with Crohn’s disease. J Crohns Colitis. 2016;10(10):1144–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Kevans D, Murthy S, Mould DR, Silverberg MS. Accelerated clearance of infliximab is associated with treatment failure in patients with corticosteroid refractory acute ulcerative colitis. J Crohns Colitis. 2018;12:662–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Oude Munnink TH, Henstra MJ, Segerink LI, Movig KL, Brummelhuis-Visser P. Therapeutic drug monitoring of monoclonal antibodies in inflammatory and malignant disease: translating TNF-α experience to oncology. Clin Pharmacol Ther. 2016;99(4):419–31.CrossRefPubMedGoogle Scholar
  15. 15.
    Mould DR. Why therapeutic drug monitoring is needed for monoclonal antibodies and how do we implement this? Clin Pharmacol Ther. 2016;99(4):351–4.CrossRefPubMedGoogle Scholar
  16. 16.
    Seow CH, Newman A, Irwin SP, Steinhart AH, Silverberg MS, Greenberg GR. Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis. Gut. 2010;59(1):49–54.CrossRefPubMedGoogle Scholar
  17. 17.
    Maser EA, Villela R, Silverberg MS, Greenberg GR. Association of trough serum infliximab to clinical outcome after scheduled maintenance treatment for Crohn’s disease. Clin Gastroenterol Hepatol. 2006;4(10):1248–54.CrossRefPubMedGoogle Scholar
  18. 18.
    Vande Casteele N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7):1320–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Reinisch W, Colombel JF, Sandborn WJ, Mantzaris GJ, Kornbluth A, Adedokun OJ, et al. Factors associated with short- and long-term outcomes of therapy for Crohn’s disease. Clin Gastroenterol Hepatol. 2015;13(3):539–47.CrossRefPubMedGoogle Scholar
  20. 20.
    Pouillon L, Ferrante M, Van Assche G, Rutgeerts P, Noman M, Sabino J, Vande Casteele N, Gils A, Vermeire S. Mucosal healing and long-term outcomes of patients with inflammatory bowel diseases receiving clinic-based vs trough concentration-based dosing of infliximab. Clin Gastroenterol Hepatol. 2017.  https://doi.org/10.1016/j.cgh.2017.11.046.
  21. 21.
    Cornillie F, Hanauer SB, Diamond RH, Wang J, Tang KL, Xu Z, et al. Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. Gut. 2014;63:1721–7.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Papamichael K, Cheifetz AS. Use of anti-TNF drug levels to optimise patient management. Frontline Gastroenterol. 2016;7(4):289–300.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Papamichael K, Casteele NV, Ferrante M, Gils A, Cheifetz AS. Therapeutic drug monitoring during induction of anti-tumor necrosis factor therapy in inflammatory bowel disease: defining a therapeutic drug window. Inflamm Bowel Dis. 2017;23(9):1510–5.CrossRefPubMedGoogle Scholar
  24. 24.
    Weiner LM. Monoclonal antibody therapy of cancer. Semin Oncol. 1999;26:43–51.PubMedGoogle Scholar
  25. 25.
    Wolbink GJ, Vis M, Lems W, Voskuyl AE, de Groot E, Nurmohamed MT, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(3):711–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Brinks V, Jiskoot W, Schellekens H. Immunogenicity of therapeutic proteins: the use of animal models. Pharm Res. 2011;28:2379–85.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schellekens H. Bioequivalence and the immunogenicity of biopharmaceuticals. Nat Rev Drug Discov. 2002;1(6):457–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Kijanka G, Jiskoot W, Schellekens H, Brinks V. Effect of treatment regimen on the immunogenicity of human interferon Beta in immune tolerant mice. Pharm Res. 2013;30(6):1553–60.CrossRefPubMedGoogle Scholar
  29. 29.
    Stephens S, Emtage S, Vetterlein O, Chaplin L, Bebbington C, Nesbitt A, et al. Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology. 1995;85(4):668–74.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Brandse JF, Mould D, Smeekes O, Ashruf Y, Kuin S, Strik A, et al. A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(4):650–60.CrossRefPubMedGoogle Scholar
  31. 31.
    Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1–110.PubMedGoogle Scholar
  32. 32.
    Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.CrossRefPubMedGoogle Scholar
  33. 33.
    Xu Z, Mould DR, Hu C, Ford J, Keen M, Davis HM, et al. Population pharmacokinetic analysis of infliximab in pediatrics using integrated data from six clinical trials abstract 139760. Clin Pharmacol Drug Dev. 2012;1(4):203.Google Scholar
  34. 34.
    Zhao Q, Tensfeldt TG, Chandra R, Mould DR. Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets. Malar J. 2014;13:36.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Brambell FW, Hemmings WA, Morris IGA. Theoretical model of gamma-globulin catabolism. Nature. 1964;203:1352–4.CrossRefPubMedGoogle Scholar
  36. 36.
    Telleman P, Junghans RP. The role of the Brambell receptor (FcRB) in liver: protection of endocytosed immunoglobulin G (IgG) from catabolism in hepatocytes rather than transport of IgG to bile. Immunology. 2000;100(2):245–51.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Morell A, Terry WD, Waldmann TA. Metabolic properties of IgG subclasses in man. J Clin Invest. 1970;49(4):673–80.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Marks J. Antibody formation in myelomatosis. J Clin Pathol. 1953;6(1):62–3.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Jacobs JFM, Mould DR. The role of FcRn in the pharmacokinetics of biologics in patients with multiple myeloma. Clin Pharmacol Ther. 2017;102(6):903–4.CrossRefPubMedGoogle Scholar
  40. 40.
    Fasanmade AA, Adedokun OJ, Blank M, Zhou H, Davis HM. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011;33(7):946–64.CrossRefPubMedGoogle Scholar
  41. 41.
    Beeken WL, Busch HJ, Sylwester DL. Intestinal protein loss in Crohn’s disease. Gastroenterology. 1972;62(2):207–15.PubMedGoogle Scholar
  42. 42.
    Kapel N, Meillet D, Favennec L, Magne D, Raichvarg D, Gobert JG. Evaluation of intestinal clearance and faecal excretion of alpha 1-antiproteinase and immunoglobulins during Crohn’s disease and ulcerative colitis. Eur J Clin Chem Clin Biochem. 1992;30:197–202.PubMedGoogle Scholar
  43. 43.
    Brandse JF, Wildenberg M, de Bruyn JR, et al. Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease. Gastroenterology. 2013;144(5):S-7763.Google Scholar
  44. 44.
    Kaneshige H. Nonenzymatic glycosylation of serum IgG and its effect on antibody activity in patients with diabetes mellitus. Diabetes. 1987;36(7):822–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics based dosing paradigms. Clin Pharmacol Ther. 2012;91:635–46.CrossRefPubMedGoogle Scholar
  46. 46.
    Steenholdt C, Brynskov J, Thomsen OO, Munck LK, Fallingborg J, Christensen LA, et al. Individualised therapy is more cost-effective than dose intensification in patients with Crohn's disease who lose response to anti-TNF treatment: a randomised, controlled trial. Gut. 2014;63:919–27.CrossRefPubMedGoogle Scholar
  47. 47.
    Dubinsky MC, Phan BL, Singh N, Rabizadeh S, Mould DR. Pharmacokinetic dashboard recommended dosing is different than standard of care dosing in infliximab treated pediatric IBD patients. AAPS J. 2017;19(1):215–22.CrossRefPubMedGoogle Scholar
  48. 48.
    Eser A, Primas C, Vogelsang H, Novacek G, Mikulits A, Reinisch S, Papay P, Lichtenberger C, Brehovsky S, Mould DR, Reinisch W. Prediction of individual serum infliximab concentrations in inflammatory bowel disease by a Bayesian dashboard system. J Clin Pharmacol. 2018.  https://doi.org/10.1002/jcph.1069.
  49. 49.
    Wojciechowski J, Upton RN, Mould DR, Wiese MD, Foster DJR. Infliximab maintenance dosing in inflammatory bowel disease: an example for in silico assessment of adaptive dosing strategies. AAPS J. 2017;19:1136–47.  https://doi.org/10.1208/s12248-017-0082-8.CrossRefPubMedGoogle Scholar
  50. 50.
    Ordás N, Ferrante M, Van Assche G, Ballet V, Compernolle G, Van Steen K, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148:1320–9.CrossRefGoogle Scholar
  51. 51.
    Vaughn BP, Martinez-Vazquez M, Patwardhan VR, Moss AC, Sandborn WJ, Cheifetz AS. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014;20(11):1996–2003.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Papamichael K, Rivals-Lerebours O, Billiet T, Vande Casteele N, Gils A, Ferrante M, et al. Long-term outcome of patients with ulcerative colitis and primary non-response to infliximab. J Crohns Colitis. 2016;10(9):1015–23.CrossRefPubMedGoogle Scholar
  53. 53.
  54. 54.
  55. 55.
    Gu T, Shah N, Deshpande G, Tang DH, Eisenberg DF. Comparing biologic cost per treated patient across indications among adult US managed care patients: a retrospective cohort study. Drugs Real World Outcomes. 2016;3(4):369–81.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis. 2010;69(5):817–21.CrossRefPubMedGoogle Scholar
  57. 57.
    Hong Y, Mager DE, Blum RA, Jusko WJ. Population pharmacokinetic/pharmacodynamic modeling of systemic corticosteroid inhibition of whole blood lymphocytes: modeling interoccasion pharmacodynamic variability. Pharm Res. 2007;24(6):1088–97.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Paul S, Del Tedesco E, Marotte H, Rinaudo-Gaujous M, Moreau A, Phelip JM, et al. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis. 2013;19(12):2568–76.CrossRefPubMedGoogle Scholar
  59. 59.
    Vande Casteele N, Mould DR, Coarse J, Hasan I, Gils A, Feagan B, et al. Accounting for pharmacokinetic variability of certolizumab pegol in patients with Crohn’s disease. Clin Pharmacokinet. 2017;56(12):1513–23.CrossRefPubMedGoogle Scholar
  60. 60.
    Mould DR. Using pharmacometrics in the development of biological therapeutic biological agents in Pharmacometrics: the science of quantitative pharmacology Editors: E. Ette and P Williams, Wiley Hoboken 2007 Chapter 41 pg 994.Google Scholar
  61. 61.
    Mould DR, Frame B. Population pharmacokinetic-pharmacodynamic modeling of biological agents: when modeling meets reality. J Clin Pharmacol. 2010;50(9 Suppl):91S–100S.CrossRefPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Projections Research Inc.PhoenixvilleUSA
  2. 2.Australian Centre for PharmacometricsUniversity of South AustraliaAdelaideAustralia
  3. 3.Pfizer, Inc.GrotonUSA
  4. 4.Icahn School of Medicine at Mount SinaiNew YorkUSA
  5. 5.Mount Sinai HospitalNew YorkUSA

Personalised recommendations