Mass balance study of [¹⁴C]SHR0302, a selective and potent JAK1 inhibitor in humans

Abstract

1. SHR0302, a selective JAK1 inhibitor developed by Jiangsu Hengrui Pharmaceutical Co., was intended for the treatment of rheumatoid arthritis. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of SHR0302 in six healthy Chinese male subjects after a single 8 mg (80 µCi) oral dose of [¹⁴C]SHR0302.

2. SHR0302 was absorbed rapidly (T_max = 0.505 h), and the average t_1/2 of the SHR0302-related components in plasma was approximately 9.18 h. After an oral dose was administered, the average cumulative excretion of the radioactive components was 100.56% ± 1.51%, including 60.95% ± 11.62% in urine and 39.61% ± 10.52% in faeces.

3. A total of 16 metabolites were identified. In plasma, the parent drug SHR0302 accounted for 90.42% of the total plasma radioactivity. In urine, SHR161279 was the main metabolite, accounting for 33.61% of the dose, whereas the parent drug SHR0302 only accounted for 5.1% of the dose. In faeces, the parent drug SHR0302 accounted for 23.73% of the dose, and SHR161279 was the significant metabolite, accounting for 5.67% of the dose. In conclusion, SHR0302-related radioactivity was mainly excreted through urine (60.95%) and secondarily through faeces (39.61%).

4. The metabolic reaction of SHR0302 in the human body is mainly through mono-oxidation and glucuronidation. The main metabolic location of SHR0302 in the human body is the pyrrolopyrimidine ring.

Keywords:

• SHR0302
• [¹⁴C]SHR0302
• radioactivity
• mass balance
• JAK1 inhibitor

Author contributions

XYG, SM, SY, YLW, CC, CZT, YZ, DFZ, and XXD were responsible for the sample analysis and writing of this manuscript; SM, YCB, HZ, and LYM designed the clinical study scheme and recruited the volunteers; SM, YCB, HZ, and LYM were responsible for the sample collection in the clinic; and KS, SF, and XHG provided the test drug and financial support.

Disclosure statement

KS, SF, and XHG are the employees of Hengrui Medicine Co., Ltd.

Additional information

Funding

The study was sponsored by Jiangsu Hengrui Medicine Co., Ltd. and financially supported in part by a grant from the National Natural Science Foundation of China [No. 81903701, No. 82104276, 82104275]. This work was also supported by the National Key New Drug Creation Special Programs [2017ZX09304-021], Key R&D Program of Jiangsu Province [BE2021644], Suzhou Health Leading Talent [GSWS2019001], the National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University [2020WSC07], and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).