Purpose: This study aimed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of SHR6508 injection, a new calcimimetic agent, in healthy Chinese subjects following single dose. Methods: This study utilized a placebo-controlled, single-dose and dose-escalation design with four dose groups (0.5 mg, 2.5 mg, 5 mg, 10 mg). The trial started with a low dose and continuing to the next dose after completion of the out-of-group safety assessment of the previous dose group. Blood samples were collected at 15 time points to measure pharmacokinetic and pharmacodynamic parameters. Safety was assessed by therapeutic emergency adverse events (TEAEs), clinical laboratory tests, vital signs, electrocardiograms (ECGs), and physical examination. Results: Of the 22 subjects who completed this study, 16 received SHR6508 Injection and 6 received placebo. In the 0.5-5 mg group Tmax was 0.033 - 0.058 h, and t1/2z was 8.8 h-28.3 h. Cmax and AUC increased proportionally with dose. PD results showed that SHR6508 dose-dependently decreased iPTH and blood calcium levels in subjects in the 0.5-5 mg dose range; blood phosphorus levels in subjects in the 5 mg group tended to be elevated compared to those in the placebo group. 21 TEAEs occurred in 12 subjects (54.5%), and no serious or severe TEAE occurred. Conclusion: The overall safety and tolerability of a single intravenous dose of 0.5-5 mg SHR6508 in healthy subjects was favorable, exhibiting dose-dependent PK and PD properties.

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.