Abstract CT132: Effect of gastric acid reduction and strong CYP3A induction/inhibition on the pharmacokinetics of ripretinib, a switch control tyrosine kinase inhibitor

Abstract Ripretinib is a tyrosine kinase inhibitor indicated for the treatment of adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with 3 or more kinase inhibitors, including imatinib. In a phase 1 study in patients with advanced malignancies, the maximum tolerated dose was not reached at doses up to 200 mg twice daily (BID). Dose escalation to ripretinib 150 mg BID was offered in the phase 1 and phase 3 clinical studies after radiologic disease progression at 150 mg once daily (QD) and was well tolerated with a similar safety profile as seen with 150 mg QD (approved dose regimen). Ripretinib solubility is pH dependent and ripretinib and its active metabolite (DP-5439) are cleared via CYP3A4/5; thus, drug-drug interactions (DDIs) with acid-reducing agents and strong CYP3A inhibitors/inducers were assessed. Here, we report the effects of pantoprazole (proton pump inhibitor), itraconazole (strong CYP3A inhibitor) and rifampin (strong CYP3A inducer) on the pharmacokinetics (PK) of ripretinib and DP-5439. Ripretinib PK is generally dose proportional within 50-150 mg. For each interaction, single oral doses of ripretinib (either 50 mg for pantoprazole and itraconazole or 100 mg for rifampin) were given before and concurrently with multiple doses of each perpetrator agent to healthy volunteers: pantoprazole 40 mg QD x 7 days (n = 25), itraconazole 200 mg QD x 10 days (n = 20), and rifampin 600 mg QD x 14 days (n = 24). Serial blood samples were collected over 4-7 days before and after each perpetrator drug; plasma concentrations of ripretinib and DP-5439 were determined by validated LC-MS/MS. The geometric least-squares mean (GLSM) ratios of PK parameters (i.e., AUC0-∞ and Cmax) and corresponding 90% confidence intervals (CIs) were calculated. No DDI was observed between ripretinib and pantoprazole. The ratios of GLSM and 90% CIs for AUC0-∞ and Cmax were within the bioequivalence 80%−125% range for ripretinib with pantoprazole vs ripretinib alone. Concomitant itraconazole increased exposure to ripretinib and DP-5439; GLSM ratios for ripretinib AUC0-∞ and Cmax were 199% and 136%, respectively, and similar ratios were noted for DP-5439. Exposure to ripretinib and DP-5439 based on AUC0-∞ decreased with rifampin coadministration. GLSM ratios for ripretinib AUC0-∞ and Cmax were 39% and 82%, respectively, for ripretinib with rifampin vs ripretinib alone, and were 43% and 137% for DP-5439. No dose adjustments are required when ripretinib is coadministered with either gastric acid reducers or strong CYP3A inhibitors, based on the magnitude of DDI PK effects in healthy volunteers, and the safety profile of ripretinib observed in patients and healthy volunteers. However, as decreased exposure may reduce the antitumor activity of ripretinib, concomitant use of strong CYP3A inducers with ripretinib should be avoided. Citation Format: Xiaoyan Li, Mark J. Shelton, Julie Meade, Cherie Taglienti, Constance Barysauskas, Rodrigo Ruiz-Soto, Jing Wang. Effect of gastric acid reduction and strong CYP3A induction/inhibition on the pharmacokinetics of ripretinib, a switch control tyrosine kinase inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT132.