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Introduction <p>Ripretinib, an oral switch-control inhibitor of KIT tyrosine kinase and platelet-derived growth factor receptor alpha kinase, is approved for adults with advanced gastrointestinal stromal tumor who received prior treatment with three or more kinase inhibitors, including imatinib. Ripretinib is metabolized into the equally active major metabolite DP-5439, a prominent component of total drug exposure in humans after oral administration. Ripretinib and DP-5439 undergo hepatic metabolism mainly via cytochrome P450&#xa0;3A4. Therefore, exposure to ripretinib and/or DP-5439 may be affected in patients with hepatic impairment.</p> Methods <p>This is a phase&#xa0;1, open-label study evaluating the pharmacokinetics and safety of ripretinib and DP-5439 in participants with varying degrees of hepatic impairment compared with matched healthy participants after a single oral 50-mg ripretinib dose.</p> Results <p>Mild hepatic impairment did not affect exposure to ripretinib and DP-5439. In participants with moderate and severe hepatic impairment, ripretinib exposure (area under the concentration–time curve) was 99% and 163% greater, respectively, compared with matched healthy participants, whereas DP-5439 exposure was approximately 20% greater in moderate and 44% lower in severe hepatic impairment. Exposure to combined ripretinib + DP-5439 was higher by approximately 51% and 37% in participants with moderate and severe hepatic impairment, respectively. No safety signals were identified.</p> Conclusion <p>On the basis of the known safety profile of ripretinib, these increased ripretinib and combined ripretinib + DP-5439 exposures in participants with hepatic impairment are unlikely to be clinically relevant. Therefore, no dose adjustments are recommended for patients with gastrointestinal stromal tumor and hepatic impairment.</p>

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Pharmacokinetics and Safety of Ripretinib in Participants with Hepatic Impairment: A Phase 1 Study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月20日

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  • Anna Papinska,
  • Lakshmi Viswanathan,
  • Qiang Lu,
  • Farida Abane,
  • Charles Psoinos,
  • Rodrigo Ruiz-Soto

摘要

Introduction

Ripretinib, an oral switch-control inhibitor of KIT tyrosine kinase and platelet-derived growth factor receptor alpha kinase, is approved for adults with advanced gastrointestinal stromal tumor who received prior treatment with three or more kinase inhibitors, including imatinib. Ripretinib is metabolized into the equally active major metabolite DP-5439, a prominent component of total drug exposure in humans after oral administration. Ripretinib and DP-5439 undergo hepatic metabolism mainly via cytochrome P450 3A4. Therefore, exposure to ripretinib and/or DP-5439 may be affected in patients with hepatic impairment.

Methods

This is a phase 1, open-label study evaluating the pharmacokinetics and safety of ripretinib and DP-5439 in participants with varying degrees of hepatic impairment compared with matched healthy participants after a single oral 50-mg ripretinib dose.

Results

Mild hepatic impairment did not affect exposure to ripretinib and DP-5439. In participants with moderate and severe hepatic impairment, ripretinib exposure (area under the concentration–time curve) was 99% and 163% greater, respectively, compared with matched healthy participants, whereas DP-5439 exposure was approximately 20% greater in moderate and 44% lower in severe hepatic impairment. Exposure to combined ripretinib + DP-5439 was higher by approximately 51% and 37% in participants with moderate and severe hepatic impairment, respectively. No safety signals were identified.

Conclusion

On the basis of the known safety profile of ripretinib, these increased ripretinib and combined ripretinib + DP-5439 exposures in participants with hepatic impairment are unlikely to be clinically relevant. Therefore, no dose adjustments are recommended for patients with gastrointestinal stromal tumor and hepatic impairment.