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Determination of IL-23 Pharmacokinetics by Highly Sensitive Accelerator Mass Spectrometry and Subsequent Modeling to Project IL-23 Suppression in Psoriasis Patients Treated with Anti-IL-23 Antibodies

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Abstract

The pro-inflammatory cytokine interleukin (IL)-23 is a key modulator of the immune response, making it an attractive target for the treatment of autoimmune disease. Correspondingly, several monoclonal antibodies against IL-23 are either in development or approved for autoimmune indications such as psoriasis. Despite being a clinical validated target, IL-23 pharmacokinetics (e.g., IL-23 synthesis and elimination rates) and the degree of target suppression (i.e., decrease in free “active” IL-23) associated with clinical efficacy are not well understood, primarily due to its ultra-low circulating levels and the lack of sensitive and accurate measurement methods. In the current work, this issue was overcome by using accelerator mass spectrometry (AMS) to measure the concentration and pharmacokinetics of human recombinant [14C]-IL-23 following an intravenous trace-dose in cynomolgus monkeys. IL-23 pharmacokinetic parameters along with clinical drug exposure and IL-23 binding affinities from four different anti-IL-23 antibodies (ustekinumab, tildrakizumab, guselkumab, and risankizumab) were used to build a pharmacokinetics/pharmacodynamics (PK/PD) model to assess the time course of free IL-23 over one year in psoriasis patients following different dosing regimens. The predicted rank order of reduction of free IL-23 was consistent with their reported rank order of Psoriasis Area and Severity Index (PASI) 100 scores in clinical efficacy trials (ustekinumab < tildrakizumab < guselkumab < risankizumab), thus demonstrating the utility of highly sensitive AMS for determining target pharmacokinetics to inform PK/PD modeling and assessing target suppression associated with clinical efficacy.

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Acknowledgments

The authors would like to thank Xceleron for the AMS measurements and helpful discussions. The authors wish to thank Jeff Barbon and Meha Chhaya from AbbVie Bioresearch Center (ABC) for providing the HeLa bioassay and guidance on study design, Yu Tian and Kim Youngjae from ABC for bioanalytical support, Yuni Fang and Vivian V. Zhao from AbbVie Redwood City for providing the IL-23 level in monkeys and healthy volunteers, and Colin J. Phipps from AbbVie for the review of modeling and helpful discussions. Finally, we gratefully acknowledge Candace Graff and Melanie C. Ruzek for their critical review of the manuscript.

Funding

AbbVie provided funding for AMS analysis by the contract lab Xceleron (Pharmaron).

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Authors and Affiliations

  1. DMPK, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts, USA

    Ting-Ting Zhang

  2. DMPK-BA, AbbVie, Inc., North Chicago, Illinois, USA

    Junli Ma, Gary J. Jenkins, Stella Doktor & J. Cory Kalvass

  3. Proteinaceous, Inc., Evanston, Illinois, USA

    Kenneth R. Durbin

  4. Process R&D, AbbVie, Inc., North Chicago, Illinois, USA

    Timothy Montavon

  5. Immuno-oncology, AbbVie, Inc., Redwood City, California, USA

    Susan E. Lacy

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Junli Ma, Timothy Montavon, Susan E. Lacy, Gary J. Jenkins, Stella Doktor, and J. Cory Kalvass are employees of AbbVie. Kenneth R. Durbin is a former AbbVie employee and is now an employee of Proteinaceous Inc., and has no other conflict of interest to disclose. Ting-Ting Zhang is a former AbbVie employee and is now an employee of Takeda Pharmaceuticals International Co., and has no other conflict of interest to disclose. All authors may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.

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Zhang, TT., Ma, J., Durbin, K.R. et al. Determination of IL-23 Pharmacokinetics by Highly Sensitive Accelerator Mass Spectrometry and Subsequent Modeling to Project IL-23 Suppression in Psoriasis Patients Treated with Anti-IL-23 Antibodies. AAPS J 21, 82 (2019). https://doi.org/10.1208/s12248-019-0352-8

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