Dashboards for Therapeutic Monoclonal Antibodies: Learning and Confirming
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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 WORDSBayes dashboard IBD individualized dosing monoclonal antibodies
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.
- 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
- 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.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
- 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.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
- 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.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
- 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
- 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
- 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.
- 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
- 53.FDA Exposure Response Guidance https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm072109.pdf. Accessed 2/10/2018.
- 54.Infliximab package insert https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf. Accessed 2/20/2018.
- 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
- 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