AUTHOR=Gu Xiaoting , Li Xiaohe , Tian Weixue , Zheng Chaoyue , Cai Yutian , Xu Xiang , Zhao Conglu , Liu Hongting , Sun Yao , Luo Zhilin , Zhu Shuwen , zhou Honggang , Ai Xiaoyu , Yang Cheng 

TITLE=Preclinical pharmacokinetic studies and prediction of human PK profiles for Deg-AZM, a clinical-stage new transgelin agonist

JOURNAL=Frontiers in Pharmacology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1423175

DOI=10.3389/fphar.2024.1423175

ISSN=1663-9812

ABSTRACT=<sec><title>Introduction</title><p>Deglycosylated azithromycin (Deg-AZM), a newly developed Class I drug with good therapeutic effects on slow transit constipation, is a small-molecule transgelin agonist that has been approved for clinical trials in 2024. The preclinical pharmacokinetic profile of Deg-AZM was investigated to support further development.</p></sec><sec><title>Methods</title><p>A LC-MS/MS method was established and validated to detected the concentration of Deg-AZM in various biological samples. <italic>In vivo</italic> tests such as pharmacokinetic studies in rats and dogs, tissue distribution studies in rats, and extraction studies in rats were conducted to investigated the preclinical pharmacokinetic behaviors of Deg-AZM comprehensively. The plasma protein rate of Deg-AZM was determined by rapid equilibrium dialysis method <italic>in vitro</italic>. The metabolic stability and metabolite profile of Deg-AZM was assessed using pooled mice, rats, dogs, monkeys and humans microsomes <italic>in vitro</italic>. The PK profiles of Deg-AZM in human was predicted based on physiologically based pharmacokinetic (PBPK) models.</p></sec><sec><title>Results</title><p>The plasma protein binding rates of Deg-AZM were lower in mice and rats, higher in dogs, and moderate in humans. The metabolic process of Deg-AZM was similar in rat and human liver microsomes. From Pharmacokinetic studies in rats and dogs, Deg-AZM was rapidly absorbed into the blood and then quickly eliminated. Plasma exposure of Deg-AZM was dose dependent with no accumulation after continuous gavage administration. In addition, there is no significant gender difference in the pharmacokinetic behavior of Deg-AZM. Deg-AZM was widely distributed in the tissues without obvious accumulation, and mainly excreted from the urinary excretion pathway. Furthermore, the pharmacokinetic profiles of Deg-AZM in humans showed dose dependency.</p></sec><sec><title>Conclusion</title><p>The pharmacokinetic profiles of Deg-AZM was fully explored, these results could provide valuable information to support the first-in-human dosage prediction and phase I clinical design.</p></sec>