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The safety, pharmacokinetics, and pharmacodynamics of SHR2285, an oral small molecule factor XIa inhibitor, in healthy volunteers
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  • Junyu Xu,
  • nan Zhao,
  • Jie Huang,
  • Jinlei Li,
  • Xia Zhao,
  • Qian Xiang,
  • Sibo Yang,
  • Yanli Dong,
  • Honghui Wang,
  • Yijing Li,
  • Guoping Yang,
  • Yi Min Cui
Junyu Xu
Peking University First Hospital
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nan Zhao
Peking University First Hospital
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Jie Huang
Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha 410013, China
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Jinlei Li
Central South University Third Xiangya Hospital
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Qian Xiang
Peking University First Hospital
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Sibo Yang
Central South University Third Xiangya Hospital
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Yanli Dong
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Honghui Wang
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
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Yijing Li
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
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Guoping Yang
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Yi Min Cui
Peking University First Hospital

Corresponding Author:[email protected]

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Abstract

Aim: The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in Chinese healthy volunteers. Methods: The study consisted of single ascending doses part (part A: 25 - 600 mg) and multiple ascending doses part (part B: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo. Plasma and urine samples were collected to describe its pharmacokinetics and pharmacodynamics (PD) profile. Results: SHR2285 were well tolerated. SHR2285 was absorbed rapidly with median Tmax of 1.50 to 3.00 h. The geometric median of t1/2 of SHR2285 varied from 8.74-12.1 h across 25 to 600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77-3.61 fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7 with low accumulation ratio (0.956-1.20 and 1.18-1.56 respectively). The increase in PK exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure dependent prolongation of APTT, and decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100 to 400 mg, respectively. Conclusions: SHR2285 exhibit a predictable PK profile and exposure related PD profile. These results suggest that SHR2285 is a promising novel oral FXI inhibitor warranting further evaluation.