期刊
CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT
卷 11, 期 10, 页码 1165-1176出版社
WILEY
DOI: 10.1002/cpdd.1110
关键词
drug-drug interaction; ripretinib; CYP3A inducer; CYP3A inhibitor; proton pump inhibitor
资金
- Deciphera Pharmaceuticals, LLC (Waltham, MA, USA)
- Deciphera Pharmaceuticals, LLC
This study evaluated the drug-drug interaction potentials of Ripretinib with itraconazole, rifampin, and pantoprazole. The results showed that concomitant use of itraconazole increased Ripretinib exposure, while concomitant use of rifampin decreased Ripretinib exposure, and pantoprazole coadministration had no effect on Ripretinib pharmacokinetics.
Ripretinib is a switch control KIT kinase inhibitor approved for treatment of adults with advanced gastrointestinal stromal tumors who received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib and its active metabolite (DP-5439) are cleared mainly via cytochrome P450 enzyme 3A4/5 (CYP3A4/5), and ripretinib solubility is pH-dependent, thus the drug-drug interaction potentials of ripretinib with itraconazole (strong CYP3A inhibitor), rifampin (strong CYP3A inducer), and pantoprazole (proton pump inhibitor) were each evaluated in open-label, fixed-sequence study designs. Overall, 20 participants received ripretinib 50 mg alone and with itraconazole 200 mg once daily, 24 participants received ripretinib 100 mg alone and with rifampin 600 mg once daily, and 25 participants received ripretinib 50 mg alone and with pantoprazole 40 mg once daily. Ripretinib exposure increased with concomitant itraconazole, with geometric least-squares (LS) mean ratios of ripretinib area under the concentration-time curve from 0 to infinity (AUC(0-infinity)) and maximum observed concentration (C-max) of 199% and 136%. Ripretinib exposure decreased with concomitant rifampin: geometric LS mean ratios for ripretinib AUC(0-infinity) and C-max were 39% and 82%. Pantoprazole coadministration had no effect on ripretinib pharmacokinetics. No unexpected safety signals occurred. No dose adjustment is required for ripretinib coadministered with gastric acid reducers and strong CYP3A inhibitors; patients also receiving strong CYP3A inhibitors should be monitored more frequently for adverse reactions. Concomitant ripretinib use with strong CYP3A inducers should be avoided. Prescribers should refer to approved labeling for specific dose recommendations with concomitant use of strong and moderate CYP3A inducers.
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