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Impact of Organ Impairment on the Pharmacokinetics of Therapeutic Peptides and Proteins

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Abstract

The kidneys and liver are major organs involved in eliminating small-molecule drugs from the body. Characterization of the effects of renal impairment (RI) and hepatic impairment (HI) on pharmacokinetics (PK) have informed dosing in patients with these organ impairments. However, the knowledge about the impact of organ impairment on therapeutic peptides and proteins is still evolving. In this study, we reviewed how often therapeutic peptides and proteins were assessed for the effect of RI and HI on PK, the findings, and the resulting labeling recommendations. RI effects were reported in labeling for 30 (57%) peptides and 98 (39%) proteins and HI effects for 20 (38%) peptides and 55 (22%) proteins. Dose adjustments were recommended for RI in 11 of the 30 (37%) peptides and 10 of the 98 (10%) proteins and for HI in 7 of the 20 (35%) peptides and 3 of the 55 (5%) proteins. Additional actionable labeling includes risk mitigation strategies; for example, some product labels have recommended avoid use or monitor toxicities in patients with HI. Over time, there is an increasing structural diversity of therapeutic peptides and proteins, including the use of non-natural amino acids and conjugation technologies, which suggests a potential need for reassessing the need to evaluate the effect of RI and HI. Herein, we discuss scientific considerations for weighing the risk of PK alteration due to RI or HI for peptide and protein products. We briefly discuss other organs that may affect the PK of peptides and proteins administered via other delivery routes.

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Acknowledgements

The authors acknowledge Dr. Rajanikanth Madabushi for the review of the manuscript, Cara Carter and Westley Eure for collecting the survey data related to peptides, and colleagues in the Office of Clinical Pharmacology through their review contributions that provided pharmacokinetics information in organ-impaired subjects which form the basis of this study.

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Authors and Affiliations

  1. Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA

    Elimika Pfuma Fletcher, Martina Sahre, Anand Balakrishnan, Lin Zhou, Qin Sun, Jie Wang, Raajan Naik, Shiew Mei Huang & Yow-Ming C. Wang

  2. Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, Office of New Drug, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

    Yuen Yi Hon

  3. Office of Therapeutic Biologics and Biosimilars, Office of New Drug, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

    Kimberly Maxfield

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  1. Elimika Pfuma Fletcher
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  2. Martina Sahre
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All authors have contributed equally to the manuscript preparation.

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Correspondence to Yow-Ming C. Wang.

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Fletcher, E.P., Sahre, M., Hon, Y.Y. et al. Impact of Organ Impairment on the Pharmacokinetics of Therapeutic Peptides and Proteins. AAPS J 25, 54 (2023). https://doi.org/10.1208/s12248-023-00819-0

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