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Effect of SHR0302 on the Pharmacokinetics of CYP3A4, CYP2C8, CYP2C9, and CYP2C19 Probe Substrates in Healthy Volunteers: A Cocktail Analysis
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  • Meng Fu,
  • Lin Luo,
  • Sheng Feng,
  • Hongda Lin,
  • Zekun Lu,
  • Fei Gu,
  • Yang Fan,
  • Bing Wu,
  • Jianying Huang,
  • Kai Shen
Meng Fu
Jiangsu Hengrui Pharmaceuticals Co Ltd
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Sheng Feng
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Hongda Lin
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Jianying Huang
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Kai Shen
Jiangsu Hengrui Medicine Co Ltd

Corresponding Author:kai.shen@hengrui.com

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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.
24 Mar 2023Submitted to British Journal of Clinical Pharmacology
24 Mar 2023Assigned to Editor
24 Mar 2023Submission Checks Completed
24 Mar 2023Review(s) Completed, Editorial Evaluation Pending
12 Apr 2023Reviewer(s) Assigned
16 May 2023Editorial Decision: Revise Minor
12 Jun 20231st Revision Received
13 Jun 2023Assigned to Editor
13 Jun 2023Submission Checks Completed
13 Jun 2023Review(s) Completed, Editorial Evaluation Pending
23 Jun 2023Editorial Decision: Revise Minor
02 Jul 20232nd Revision Received
02 Jul 2023Assigned to Editor
02 Jul 2023Submission Checks Completed
02 Jul 2023Review(s) Completed, Editorial Evaluation Pending
06 Jul 2023Editorial Decision: Accept