Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein.

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  • Additional Information
    • Source:
      Publisher: Frontiers Media] Country of Publication: Switzerland NLM ID: 101548923 Publication Model: eCollection Cited Medium: Print ISSN: 1663-9812 (Print) Linking ISSN: 16639812 NLM ISO Abbreviation: Front Pharmacol Subsets: PubMed not MEDLINE
    • Publication Information:
      Original Publication: [Lausanne : Frontiers Media]
    • Abstract:
      Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC 50 for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (K d ) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC 50 by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro K d . The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2-3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein.
      Competing Interests: All authors are current or former employees of Bristol Myers Squibb and own or previously owned the company’s stocks.
      (Copyright © 2022 Yang, Loy, Poirson, Dai, Rajendran, Xu, Spires, Gururajan, Lin, Arbanas, Carl, Pace, Wang, Mehl, Vasudevan, Spires, Novosiadly, Coker, Perez, Covello, Morin, Graziano, Broz and Lehman-McKeeman.)
    • References:
      Front Immunol. 2020 Mar 24;11:487. (PMID: 32265932)
      Pharm Res. 2014 Jul;31(7):1823-33. (PMID: 24464271)
      Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2745-51. (PMID: 17008587)
      Toxicol Pathol. 2003 Sep-Oct;31(5):554-61. (PMID: 14692624)
      Annu Rev Immunol. 2001;19:683-765. (PMID: 11244051)
      Cancer Res. 2012 Jul 15;72(14):3570-81. (PMID: 22581824)
      Nat Rev Drug Discov. 2012 Oct;11(10):751-61. (PMID: 22935759)
      J Exp Med. 2000 Oct 2;192(7):1027-34. (PMID: 11015443)
      J Clin Oncol. 2016 Oct 10;34(29):3562-3569. (PMID: 27528724)
      Regul Toxicol Pharmacol. 2002 Feb;35(1):56-71. (PMID: 11846636)
      PLoS One. 2011;6(9):e25210. (PMID: 21969873)
      Gastroenterology. 2000 Dec;119(6):1473-82. (PMID: 11113068)
      Ann Biomed Eng. 2002 Jul-Aug;30(7):961-8. (PMID: 12398426)
      PLoS One. 2008 Jun 11;3(6):e2404. (PMID: 18545704)
      Arterioscler Thromb Vasc Biol. 2007 Dec;27(12):2743-9. (PMID: 17951325)
      Cancer Med. 2013 Oct;2(5):662-73. (PMID: 24403232)
      J Young Pharm. 2010 Jul;2(3):332-6. (PMID: 21042496)
      Cancer Res. 2017 Dec 1;77(23):6667-6678. (PMID: 28993412)
      Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4265-73. (PMID: 16857801)
      Hum Vaccin Immunother. 2020 Oct 2;16(10):2328-2332. (PMID: 32159421)
      Cancer Cell. 2018 Nov 12;34(5):775-791.e3. (PMID: 30423297)
      Gastroenterology. 2000 Dec;119(6):1461-72. (PMID: 11113067)
      Blood. 1996 Jan 15;87(2):699-705. (PMID: 8555493)
      Clin Diagn Lab Immunol. 2002 Jul;9(4):777-83. (PMID: 12093672)
      Front Immunol. 2016 Feb 02;7:21. (PMID: 26870037)
      Drug Metab Dispos. 2022 Jul;50(7):898-908. (PMID: 35545256)
      J Clin Pharmacol. 2017 Jun;57(6):690-703. (PMID: 28387940)
    • Contributed Indexing:
      Keywords: Fc-fusion protein; IL-10; IL-18; anemia (therapy); pharmacodynamic biomarker; pharmacokinetic/pharmacodynamic modeling; therapeutic index; thrombocytopenia (therapy)
    • Publication Date:
      Date Created: 20220707 Latest Revision: 20220716
    • Publication Date:
      20240105
    • Accession Number:
      PMC9251408
    • Accession Number:
      10.3389/fphar.2022.829063
    • Accession Number:
      35795558