Avapritinib Carries the Risk of Drug Interaction via Inhibition of UDP-Glucuronyltransferase (UGT) 1A1

Abstract

Background: Avapritinib is the only drug for adult patients with PDGFRA exon 18 mutated unresectable or metastatic Gastrointestinal Stromal Tumor (GIST). Although avapritinib has been approved by the FDA for three years, little is known about the risk of Drug-drug Interac-tions (DDIs) via UDP-glucuronyltransferases (UGTs) inhibition. Objective: The aim of the present study was to systematically evaluate the inhibitory effects of avapritinib against UGTs and to quantitatively estimate its potential DDIs risk in vivo. Methods: Recombinant human UGTs were employed to catalyze the glucuronidation of sub-strates in a range of concentrations of avapritinib. The kinetics analysis was performed to evaluate the inhibition types of avapritinib against UGTs. The quantitative prediction of DDIs was done using In vitro-in vivo Extrapolation (IVIVE). Results: Avapritinib had a potent competitive inhibitory effect on UGT1A1. Quantitative predic-tion results showed that avapritinib administered at clinical doses might result in a 14.85% in-crease in the Area Under the Curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44. result: Avapritinib exhibited a potently competitive inhibition against UGT1A1 with a Ki, u value of 3.46 ± 0.30 μM. Quantitative prediction of DDI risk model indicated that avapritinib administered at 300 mg/day might result in a 14.85% area increase in under the plasma concentration-time curve (AUC) of drugs mainly metabolizing by UGT1A1, implying low risk of interaction via liver metabolism in liver; and Rgut value of 697.02 was much higher than 11 in UGT1A1, indicating a high risk of DDI in intestine. Conclusion: Avapritinib has the potential to cause intestinal DDIs via the inhibition of UGT1A1. Additional attention should be paid when avapritinib is coadministered with UGT1A1 substrates. other: no