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

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY Current drug metabolism Pub Date : 2024-01-01 DOI:10.2174/0113892002288312240521092054

Xin Lv, Zhen Wang, Zhe Wang, Hang Yin, Yangliu Xia, Lili Jiang, Yong Liu

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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 interactions (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 substrates 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 prediction results showed that avapritinib administered at clinical doses might result in a 14.85% increase 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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阿伐替尼有通过抑制 UDP-Glucuronosyltransferase (UGT) 1A1 发生药物相互作用的风险。

背景：阿伐替尼是治疗PDGFRA外显子18突变的不可切除或转移性胃肠道间质瘤（GIST）成人患者的唯一药物。尽管阿伐替尼已获美国食品药品管理局批准三年，但人们对其通过抑制UDP-葡萄糖醛酸转移酶（UGTs）而导致的药物间相互作用（DDIs）风险知之甚少：本研究旨在系统评估阿伐替尼对UGTs的抑制作用，并定量估计其在体内潜在的DDIs风险：方法：采用重组人 UGTs 催化阿伐替尼在一定浓度范围内的亚底物葡萄糖醛酸化反应。方法：采用重组人 UGTs 催化阿伐替尼在一定浓度范围内的葡萄糖醛酸化作用，并进行动力学分析以评估阿伐替尼对 UGTs 的抑制类型。采用体外-体内外推法（IVIVE）对DDIs进行了定量预测：结果：阿伐替尼对UGT1A1具有强效竞争性抑制作用。定量预测结果显示，按临床剂量服用阿伐替尼可能会导致主要由 UGT1A1 清除的药物的曲线下面积（AUC）增加 14.85%。此外，计算得出的Rgut值为18.44：阿伐替尼有可能通过抑制 UGT1A1 而导致肠道 DDI。结论：阿伐普替尼有可能通过抑制 UGT1A1 导致肠道 DDIs，因此在阿伐普替尼与 UGT1A1 底物联合用药时应格外注意。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.