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Population pharmacokinetics and pharmacodynamics of efmarodocokin alfa (IL-22Fc)

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Abstract

Efmarodocokin alfa (IL-22Fc) is a fusion protein of human IL-22 linked to the crystallizable fragment (Fc) of human IgG4. It has been tested in multiple indications including inflammatory bowel disease (IBD). The purposes of the present analyses were to describe the population pharmacokinetics (PK) of efmarodocokin alfa and perform pharmacodynamic (PD) analysis on the longitudinal changes of the PD biomarker REG3A after efmarodocokin alfa treatment as well as identify covariates that affect efmarodocokin alfa PK and REG3A PD. The data used for this analysis included 182 subjects treated with efmarodocokin alfa in two clinical studies. The population PK and PD analyses were conducted sequentially. Efmarodocokin alfa concentration–time data were analyzed using a nonlinear mixed-effects modeling approach, and an indirect response model was adopted to describe the REG3A PD data with efmarodocokin alfa serum concentration linked to the increase in REG3A. The analysis software used were NONMEM and R. A 3-compartment model with linear elimination best described the PK of efmarodocokin alfa. The estimated population-typical value for clearance (CL) was 1.12 L/day, and volume of central compartment was 6.15 L. Efmarodocokin alfa CL increased with higher baseline body weight, C-reactive protein, and CL was 27.6% higher in IBD patients compared to healthy subjects. The indirect response PD model adequately described the longitudinal changes of REG3A after efmarodocokin alfa treatment. A popPK and PD model for efmarodocokin alfa and REG3A was developed and covariates affecting the PK and PD were identified.

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Acknowledgements

This study was sponsored by Genentech, Inc. The authors would like to thank the patients who participated in this study, their families, the study coordinators, and the support staff at the clinical sites.

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This study was sponsored by Genentech Inc.

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Authors and Affiliations

  1. Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA

    Yanke Yu, Michael E. Rothenberg, Han Ting Ding, Gizette Sperinde, Brandon Harder, Rong Zhang, Ryan Owen, Nastya Kassir & Annemarie N. Lekkerkerker

  2. Pharmetheus AB, Uppsala, Sweden

    Ari Brekkan

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  1. Yanke Yu
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YY and AB conducted the analysis; YY and AL wrote the main manuscript; and all authors reviewed the manuscript.

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Correspondence to Yanke Yu.

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The authors declare no competing interests. YY, MR, HD, BH, RZ, RO, NK, and AL are employees of Genentech Inc. and own stock in Roche Inc.

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Yu, Y., Rothenberg, M.E., Ding, H.T. et al. Population pharmacokinetics and pharmacodynamics of efmarodocokin alfa (IL-22Fc). J Pharmacokinet Pharmacodyn 51, 141–153 (2024). https://doi.org/10.1007/s10928-023-09888-2

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