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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

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

Author(s): Xin Lv, Zhen Wang, Zhe Wang, Hang Yin, Yangliu Xia, Lili Jiang* and Yong Liu*

Volume 25, Issue 3, 2024

Published on: 27 May, 2024

Page: [197 - 204] Pages: 8

DOI: 10.2174/0113892002288312240521092054

Price: $65

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 four 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 area under the curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44.

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.


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