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The AAPS Journal

, Volume 16, Issue 5, pp 1009–1017 | Cite as

Population Pharmacokinetic Modeling of LY2189102 after Multiple Intravenous and Subcutaneous Administrations

  • Sébastien Bihorel
  • Jill Fiedler-Kelly
  • Elizabeth Ludwig
  • Joanne Sloan-Lancaster
  • Eyas Raddad
Research Article

Abstract

Interleukin-1 beta (IL-1β) is an inflammatory mediator which may contribute to the pathophysiology of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). Population pharmacokinetics (PK) of LY2189102, a high affinity anti-IL-1β humanized monoclonal immunoglobulin G4 evaluated for efficacy in RA and T2DM, were characterized using data from 79 T2DM subjects (Study H9C-MC-BBDK) who received 13 weekly subcutaneous (SC) doses of LY2189102 (0.6, 18, and 180 mg) and 96 RA subjects (Study H9C-MC-BBDE) who received five weekly intravenous (IV) doses (0.02–2.5 mg/kg). Frequency of anti-drug antibody (ADA) development appears dose-dependent and is different between studies (36.7% in Study H9C-MC-BBDK vs. 2.1% in Study H9C-MC-BBDE), likely due to several factors, including differences in patient population and background medications, administration routes, and assays. A two-compartment model with dose-dependent bioavailability best characterizes LY2189102 PK following IV and SC administration. Typical elimination and distribution clearances, central and peripheral volumes of distribution are 0.222 L/day, 0.518 L/day, 3.08 L, and 1.94 L, resulting in a terminal half-life of 16.8 days. Elimination clearance increased linearly, yet modestly, with baseline creatinine clearance and appears 37.6% higher in subjects who developed ADA. Bioavailability (0.432–0.721) and absorption half-life (94.3–157 h) after SC administration are smaller with larger doses. Overall, LY2189102 PK is consistent with other therapeutic humanized monoclonal antibodies and is likely to support convenient SC dosing.

KEY WORDS

interleukin-1 beta (IL-1β) LY2189102 population pharmacokinetics 

REFERENCES

  1. 1.
    Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.PubMedCrossRefGoogle Scholar
  2. 2.
    Kineret (anakinra) [package insert]. Stockholm, Sweden: Swedish Orphan Biovitrum AB; 2012. http://www.kineretrx.com/fileadmin/user_upload/kineretus/documents/Kineret_Full_Prescribing_Information.pdf. Published Dec 2012. Accessed 20 Feb 2014.
  3. 3.
    Kineret (anakinra). Summary of product characteristics. 2002. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000363/WC500042310.pdf. Accessed 20 Feb 2014.
  4. 4.
    Donath MY, Weder C, Whitmore J, Bauer RJ, Der K, Scannon PJ, et al. XOMA 052, an anti–IL–1β antibody, in a double-blind, placebo-controlled, dose escalation study of the safety and pharmacokinetics in patients with type 2 diabetes mellitus—a new approach to therapy. Diabetologia. 2008;51 Suppl 1:S7.Google Scholar
  5. 5.
    Larsen CM, Faulenbach M, Vaag A, Vølund A, Ehses JA, Seifert B, et al. Interleukin–1–receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care. 2009;32(9):1663–8. doi: 10.2337/dc09-0533.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, et al. Glucose–induced beta cell production of IL–1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110(6):851–60.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Maedler K, Spinas GA, Lehmann R, Sergeev P, Weber M, Fontana A, et al. Glucose induces beta–cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes. 2001;50(8):1683–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Maedler K, Storling J, Sturis J, Zuellig RA, Spinas GA, Arkhammar PO, et al. Glucose–and interleukin–1beta induced beta–cell apoptosis requires Ca2+ influx and extracellular signal–regulated kinase (ERK) 1/2 activation and is prevented by a sulfonylurea receptor 1/inwardly rectifying K+ channel 6.2 (SUR/Kir6.2) selective potassium channel opener in human islets. Diabetes. 2004;53(7):1706–13.PubMedCrossRefGoogle Scholar
  10. 10.
    Welsh N, Cnop M, Kharroubi I, Bugliani M, Lupi R, Marchetti P, et al. Is there a role for locally produced interleukin–1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes. 2005;54(11):3238–44.PubMedCrossRefGoogle Scholar
  11. 11.
    Sloan-Lancaster J, Abu-Raddad E, Polzer J, Miller JW, Scherer JC, De Gaetano A, et al. Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes. Diabetes Care. 2013;36(8):2239–46.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Abu-Raddad E, DeGaetano A, Bihorel S, Fiedler-Kelly J, Sloan-Lancaster J. Pharmacokinetic (PK) and pharmacodynamic (PD) modeling of subcutaneous (SC) LY2189102, a neutralizing IL–1β antibody, in patients with type 2 diabetes mellitus. Diabetologia. 2011;54 Suppl 1:S366.Google Scholar
  13. 13.
    Grundy SM, Cleeman JI, Merz CN, Brewer Jr HB, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110(2):227–39.PubMedCrossRefGoogle Scholar
  14. 14.
    NONMEM [computer program]. Version VI. Ellicott City, MD: ICON Development Solutions; 2006.Google Scholar
  15. 15.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.PubMedCrossRefGoogle Scholar
  16. 16.
    Peck CC, Conner DP, Murphy MG. Bedside clinical pharmacokinetics: Simple techniques for individualized drug therapy. Vancouver: Applied Therapeutics, Inc; 1989.Google Scholar
  17. 17.
    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011;13(2):143–51. doi: 10.1208/s12248-011-9255-z.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    R Development Core Team (2010). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org.
  19. 19.
    Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633–59. doi: 10.2165/11535960-000000000-00000.PubMedCrossRefGoogle Scholar
  20. 20.
    Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493–507. doi: 10.2165/11531280-000000000-00000.PubMedCrossRefGoogle Scholar
  21. 21.
    Kagan L, Turner MR, Balu-Iyer SV, Mager DE. Subcutaneous absorption of monoclonal antibodies: Role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharm Res. 2012;29(2):490–9. doi: 10.1007/s11095-011-0578-3.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58. doi: 10.1038/clpt.2008.170.PubMedCrossRefGoogle Scholar
  23. 23.
    Porter CJ, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci. 2000;89(3):297–310.PubMedCrossRefGoogle Scholar
  24. 24.
    Swartz MA. The physiology of the lymphatic system. Adv Drug Deliv Rev. 2001;50(1–2):3–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Israel EJ, Wilsker DF, Hayes KC, Schoenfeld D, Simister NE. Increased clearance of IgG in mice that lack beta 2-microglobulin: Possible protective role of FcRn. Immunology. 1996;89(4):573–8.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Lobo ED, Hansen RJ, Balthasar JP. Antibody pharmacokinetics and pharmacodynamics. J Pharm Sci. 2004;93(11):2645–68.PubMedCrossRefGoogle Scholar
  27. 27.
    Deng R, Meng YG, Hoyte K, Lutman J, Lu Y, Iyer S, et al. Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice. MAbs. 2012;4(1):101–9. doi: 10.4161/mabs.4.1.18543.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil FP, et al. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-α antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos. 2010;38(4):600–5. doi: 10.1124/dmd.109.031310.PubMedCrossRefGoogle Scholar
  29. 29.
    Kagan L, Mager DE. Mechanisms of subcutaneous absorption of rituximab in rats. Drug Metab Dispos. 2013;41(1):248–55. doi: 10.1124/dmd.112.048496.PubMedCrossRefGoogle Scholar
  30. 30.
    Datta-Mannan A, Witcher DR, Lu J, Wroblewski VJ. Influence of improved FcRn binding on the subcutaneous bioavailability of monoclonal antibodies in cynomolgus monkeys. MAbs. 2012;4(2):267–73.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 2012;14(2):296–302. doi: 10.1208/s12248-012-9340-y.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Meibohm B, Zhou H. Characterizing the impact of renal impairment on the clinical pharmacology of biologics. J Clin Pharmacol. 2012;52 Suppl 1:S54–62. doi: 10.1177/0091270011413894.CrossRefGoogle Scholar
  33. 33.
    Food and Drug Administration. Guidance for industry: immunogenicity assessment for therapeutic protein products (draft guidance). http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338856.pdf. Published Feb 2013. Accessed 22 May 2013.
  34. 34.
    Goldsby RA, Kindt TJ, Osborne BA, Kuby J. Antigens. In: Goldsby RA, Kindt TJ, Kuby J, Osborne BA, editors. Immunology. 5th ed. New York: WH Freeman & Co Publishers; 2002. p. 57–75.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Sébastien Bihorel
    • 1
  • Jill Fiedler-Kelly
    • 1
  • Elizabeth Ludwig
    • 1
  • Joanne Sloan-Lancaster
    • 2
  • Eyas Raddad
    • 2
  1. 1.Cognigen CorporationBuffaloUSA
  2. 2.Chorus, Lilly Research Laboratories, Eli Lilly and CompanyIndianapolisUSA

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