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\begin{document}

\title{Effect of SHR0302 on the Pharmacokinetics of CYP3A4, CYP2C8, CYP2C9, and
CYP2C19 Probe Substrates in Healthy Volunteers: A Cocktail Analysis}



\author[1]{Meng Fu}%
\author[2]{Lin Luo}%
\author[2]{Sheng Feng}%
\author[2]{Hongda Lin}%
\author[2]{Zekun Lu}%
\author[2]{Fei Gu}%
\author[2]{Yang Fan}%
\author[2]{Bing Wu}%
\author[2]{Jianying Huang}%
\author[3]{Kai Shen}%
\affil[1]{Jiangsu Hengrui Pharmaceuticals Co Ltd}%
\affil[2]{Affiliation not available}%
\affil[3]{Jiangsu Hengrui Medicine Co Ltd}%


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  \date{May 22, 2024}


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\begin{abstract}
Aim: This study evaluated the effects of SHR0302 on the pharmacokinetics
of cytochrome P450 (CYP) probe substrates. Methods: We performed a
single-center, open-label, three-period drug-drug interaction (DDI)
study in 24 healthy subjects (NCT05392127). Subjects received a single
oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19), and 15
mg midazolam (CYP3A4) on day 1, 8, and 22, and received 0.5 mg
repaglinide (CYP2C8) on day 7, 14, and 28. Multiple oral doses of 8 mg
SHR0302 were administered once daily from day 8 to day 28. Results: The
exposure of S-warfarin and repaglinide were comparable before and after
SHR0302 administration. AUC of midazolam was not affected by SHR0302,
whereas the administration of SHR0302 slightly decreased the Cmax of
midazolam by 7.6\% (single dose) and 15.7\% (once daily for 14 days).
The AUC0-t, AUC0-inf, and Cmax of omeprazole were slightly decreased
after a single dose of SHR0302 by 19.2\%, 21.8\%, and 23.5\%,
respectively. In the presence of SHR0302 for 14 days, the AUC0-t,
AUC0-inf, and Cmax of omeprazole were marginally reduced by 3.0\%,
16.4\%, and 8.3\%, respectively. According to the induction mechanism of
the CYP enzyme, for the investigation of the induction effect, the
results of multiple administration of the perpetrator were more reliable
than those of the single dose. Conclusion: The results demonstrated that
co-administration of SHR0302 is unlikely to have a clinically meaningful
effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9,
and CYP2C19 in healthy subjects.%
\end{abstract}%



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