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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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- Author(s): Yang Z;Yang Z; Loy J; Loy J; Poirson B; Poirson B; Dai Y; Dai Y; Rajendran S; Rajendran S; Xu S; Xu S; Spires V; Spires V; Gururajan M; Gururajan M; Lin Z; Lin Z; Arbanas J; Arbanas J; Carl S; Carl S; Pace S; Pace S; Wang Y; Wang Y; Mehl J; Mehl J; Vasudevan K; Vasudevan K; Spires T; Spires T; Novosiadly R; Novosiadly R; Coker S; Coker S; Perez R; Perez R; Covello K; Covello K; Morin P; Morin P; Graziano R; Graziano R; Broz M; Broz M; Lehman-McKeeman L; Lehman-McKeeman L
- Source:
Frontiers in pharmacology [Front Pharmacol] 2022 Jun 20; Vol. 13, pp. 829063. Date of Electronic Publication: 2022 Jun 20 (Print Publication: 2022).- Publication Type:
Journal Article- Language:
English - Source:
- 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 (Kd ) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC50 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 Kd . 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)
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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
- Source:
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