Advertisement

The AAPS Journal

, 20:40 | Cite as

Application of Pharmacometric Analysis in the Design of Clinical Pharmacology Studies for Biosimilar Development

  • Peijuan Zhu
  • Sherwin K. B. Sy
  • Andrej Skerjanec
Tutorial

Abstract

This article provides an overview of four case studies to demonstrate the utility of pharmacometric analysis in biosimilar development to help design sensitive clinical pharmacology studies for the demonstration of biosimilarity. The two major factors that determine the sensitivity of a clinical pharmacokinetic/pharmacodynamic (PK/PD) study to demonstrate biosimilarity are the size of the potential difference to be detected (signal) and the inter-subject variability (noise), both of which can be characterized and predicted using pharmacometric approaches. To maximize the chance to detect any potential difference between the proposed biosimilar and the reference drug, the dose selected for the clinical pharmacology study should fall on the steep part of the dose-response curve. Pharmacometric analysis can be used to characterize the dose-response relationship using PD- or PK/PD-linked models. The understanding of the PD endpoints in terms of dynamic range of the response and the location of the studied dose on the dose-response curve can provide strategic advantage in the trial design. To reduce the inter-subject variability (noise), pharmacometric analysis can help avoid high variability associated with low doses, and decrease variability by controlling certain covariates in the inclusion/exclusion criteria. Pharmacometric analysis also can help select or justify margins for the equivalence test of PD endpoints. Pharmacometric analysis will assume an ever-increasing role in the clinical development of biosimilar drugs, as it helps to ensure that sufficient sensitivity is built into the study design to detect potential PK and PD differences.

KEY WORDS

biosimilar clinical pharmacology study dose-response modeling and simulation pharmacodynamics (PD) pharmacokinetics (PK) pharmacometric analysis trial design 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
  2. 2.
    FDA. Guidance for industry: scientific considerations in demonstrating biosimilarity to a reference product. https://www.fda.gov/downloads/drugs/guidances/ucm291128.pdf. Assessed 30 Nov 2017.
  3. 3.
    FDA. Guidance for industry: clinical pharmacology data to support a demonstration of biosimilarity to a reference product. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf. Assessed Nov 30, 2017.
  4. 4.
    Dodds M, Chow V, Markus R, Pérez-Ruixo JJ, Shen D, Gibbs M. The use of Pharmacometrics to optimize biosimilar development. J Pharm Sci. 2013;102(11):3908–14.  https://doi.org/10.1002/jps.23697.CrossRefPubMedGoogle Scholar
  5. 5.
    Dirks NL, Meibohm B. Population Pharmacokinetics Of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633–59.  https://doi.org/10.2165/11535960-000000000-00000.CrossRefPubMedGoogle Scholar
  6. 6.
    Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug disposition model and identifiability of model parameters. J Pharmacokinet Pharmacodyn. 2008;35(5):573–91.  https://doi.org/10.1007/s10928-008-9102-8.CrossRefPubMedGoogle Scholar
  7. 7.
    Gabrielsson, J.Weiner, D., Non-compartmental analysis, in computational toxicology: volume I, B. Reisfeld and A.N. Mayeno, Editors. 2012, Humana Press: Totowa, NJ p 377-389.Google Scholar
  8. 8.
    Sharma, A.Jusko, W.J. Characteristics of indirect pharmacodynamic models and applications to clinical drug responses. Br J Clin Pharmacol 1998; 45(3): 229–239.Google Scholar
  9. 9.
    Julious S. Sample sizes for clinical trials with normal data. Stat Med. 2004;23(12):1921–86.  https://doi.org/10.1002/sim.1783.CrossRefPubMedGoogle Scholar
  10. 10.
    Roskos LK, Lum P, Lockbaum P, Schwab G, Yang BB. Pharmacokinetic/pharmacodynamic modeling of pegfilgrastim in healthy subjects. J Clin Pharmacol. 2006;46(7):747–57.  https://doi.org/10.1177/0091270006288731.CrossRefPubMedGoogle Scholar
  11. 11.
    Hummel, J., et al., Exploratory assessment of dose proportionality: review of current approaches and proposal for a practical criterion. Vol. 8. 2009. 38–49.Google Scholar
  12. 12.
    Tabrizi MA, Tseng C-ML, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11(1–2):81–8.  https://doi.org/10.1016/S1359-6446(05)03638-X.CrossRefPubMedGoogle Scholar
  13. 13.
    Mager, D.Jusko, W. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition 2001; 28(6): 507–532.Google Scholar
  14. 14.
    Marcheselli L, Bari A, Anastasia A, Botto B, Puccini B, Dondi A, et al. Prognostic roles of absolute monocyte and absolute lymphocyte counts in patients with advanced-stage follicular lymphoma in the rituximab era: an analysis from the FOLL05 trial of the Fondazione Italiana Linfomi. Br J Haematol. 2015;169(4):544–51.  https://doi.org/10.1111/bjh.13332.CrossRefPubMedGoogle Scholar
  15. 15.
    Shanafelt TD, Kay NE, Jenkins G, Call TG, Zent CS, Jelinek DF, et al. B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood. 2009;113(18):4188–96.  https://doi.org/10.1182/blood-2008-09-176149.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Yamauchi T, et al. Prognostic effect of peripheral blood cell counts in advanced diffuse large B-cell lymphoma treated with R-CHOP-like chemotherapy: a single institution analysis. Oncol Lett. 2015;9(2):851–6.  https://doi.org/10.3892/ol.2014.2716.CrossRefPubMedGoogle Scholar
  17. 17.
    Smolen JS, Cohen SB, Tony HP, Scheinberg M, Kivitz A, Balanescu A, et al. A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis. Ann Rheum Dis. 2017;76(9):1598–602.  https://doi.org/10.1136/annrheumdis-2017-211281.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Shin D, Kim Y, Kim YS, Körnicke T, Fuhr R. A randomized, phase I pharmacokinetic study comparing SB2 and infliximab reference product (Remicade(®)) in healthy subjects. BioDrugs. 2015;29(6):381–8.  https://doi.org/10.1007/s40259-015-0150-5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Miller RG. Simultaneous statistical inference 2nd Ed. New York: Springer Verlag.Google Scholar
  20. 20.
    Tabrizi MA, Tseng C-ML, Roskos LK. Elimination Mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11(1):81–8.  https://doi.org/10.1016/S1359-6446(05)03638-X.CrossRefPubMedGoogle Scholar
  21. 21.
    FDA. Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA. https://www.fda.gov/downloads/drugs/guidances/ucm377465.pdf. Assessed 30 Nov 2017.
  22. 22.
    FDA FDA Briefing book for EP2006 filgratim biosimilar FDA Oncology Advisory Committee Meeting. http://assets.fiercemarkets.net/public/ep2006.pdf. Assessed 30 Nov, 2017.
  23. 23.
    FDA. Non-inferiority clinical trials to establish effectiveness. https://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf. Assessed 30 Nov, 2017.
  24. 24.
    Dubois A, Gsteiger S, Balser S, Pigeolet E, Steimer JL, Pillai G, et al. Pharmacokinetic similarity of biologics: analysis using nonlinear mixed-effects modeling. Clin Pharmacol Ther. 2012;91(2):234–42.  https://doi.org/10.1038/clpt.2011.216.CrossRefPubMedGoogle Scholar
  25. 25.
    Yan X, Lowe PJ, Fink M, Berghout A, Balser S, Krzyzanski W. Population pharmacokinetic and pharmacodynamic model-based comparability assessment of a recombinant human epoetin alfa and the biosimilar HX575. J Clin Pharmacol. 2012;52(11):1624–44.  https://doi.org/10.1177/0091270011421911.CrossRefPubMedGoogle Scholar
  26. 26.
    Williams JH, Hutmacher MM, Zierhut ML, Becker JC, Gumbiner B, Spencer-Green G, et al. Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab. Br J Clin Pharmacol. 2016;82(6):1568–79.  https://doi.org/10.1111/bcp.13094.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    FDA. Guidance for industry: Population Pharmacokinetics. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072137.pdf. Assessed Nov 30, 2017.

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.Novartis Pharmaceuticals CorporationEast HanoverUSA
  2. 2.Sandoz AGBaselSwitzerland

Personalised recommendations