Pharmacokinetics and Safety of Ripretinib in Participants with Hepatic Impairment: A Phase 1 Study
Year: 2025
Type: article
Study design: Clinical Trial
Abstract: 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. 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. 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. 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. The treatment being studied here is ripretinib, which is used to treat a cancer known as advanced gastrointestinal stromal tumor. In the body, ripretinib is primarily broken down by the liver, so patients whose liver does not function well may have different experiences after taking ripretinib. This study compared how ripretinib was broken down in healthy participants and in those with decreasing levels of liver function (mild, moderate, or severe) by measuring how much ripretinib was in their blood over time. The results showed that a mild decrease in liver function did not affect how much ripretinib was in the blood. Moderate and severe decreases in liver function affected how much ripretinib was in the blood, but these changes are not expected to cause any meaningful differences in how ripretinib works or its safety profile. Side effects were similar between healthy participants and those with all levels of decreased liver function. No change in the ripretinib dose is recommended in patients with decreased liver function (mild, moderate, or severe).
Source: Advances in Therapy
Institution: Deciphera Pharmaceuticals (United States)
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funder: Deciphera Pharmaceuticals
OpenAlex ID: W4412500582