Effect of hepatic impairment on the pharmacokinetics of ripretinib.

Abstract

e16031 Background: Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of patients with advanced gastrointestinal stromal tumor who have received prior treatment with ≥3 kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are CYP3A substrates and coadministration with itraconazole (CYP3A inhibitor) increased exposure to each analyte by ̃100%. Therefore, we studied ripretinib in subjects with varying degrees of hepatic impairment (HI). Methods: Subjects with mild, moderate, and severe HI based on Child-Pugh, and matched healthy subjects received a single oral dose of ripretinib (50 mg, fasting) with 8 days of PK sampling. Concentrations of ripretinib and DP-5439 in plasma were measured by a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay. PK parameters were calculated using Phoenix WinNonlin, and the geometric least squares mean ratios and corresponding 90% confidence intervals of Cmax, AUC0-t, and AUC0-∞ (total and unbound) were calculated. Unbound concentrations were assessed at Tmax and 24 hours postdose. Results: Eight subjects with mild HI, 8 with moderate HI, 4 with severe HI, and 13 healthy matches were enrolled. As shown in the table, total ripretinib and DP-5439 PK was comparable for mild HI vs. healthy matches. For moderate HI, total ripretinib AUC was ̃100% higher (Cmax was comparable), whereas DP-5439 AUC was marginally higher (Cmax was 32% lower). For severe HI, total ripretinib AUC0-t was ̃160% higher and Cmax was ̃24% lower, whereas DP-5439 AUCs were ̃50% lower and Cmax was 78% lower. Unbound fraction was < 0.6% for ripretinib and 0.2-1.4% for DP-5439, with no clear trend with HI severity. The safety profile in HI subjects was similar to healthy matches; common adverse events (in ≥2 subjects) included increased lipase or amylase, diarrhea, and headache. Conclusions: Consistent with current labeling, mild HI had no impact on total PK. In this study, moderate and severe HI increased ripretinib AUC ̃100% and 163%, respectively. PK exposure to DP-5439 and combined ripretinib + DP-5439 was impacted to a lesser extent. Dose recommendations in moderate and severe HI are currently under development.[Table: see text]