Pharmacokinetics and Safety of HRS-1780 in Renal Impaired Subjects: A Multicenter, Non-Randomized, Open-Label Study

Yue Fei,1 Zhihong Xie,2 Yuanyuan Luo,3 Xiaolan Yong,4 Na Li,1 Rong Huang,1 Xiaolin Du,4 Yijing Zhu,4 Dongmei Lan,3 Yang Qi,3 Gang Cheng,1 Quanren Wang,1 Kai Shen1 1Department of Clinical Research, Jiangsu Hengrui Pharmaceuticals, Shanghai, People’s Republic of China; 2Phase I Clinical Trial Center, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 3Phase I Clinical Trial Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, People’s Republic of China; 4Phase I Clinical Trial Center, Chengdu Xinhua Hospital, Chengdu, People’s Republic of ChinaCorrespondence: Kai Shen, Department of Clinical Research, Jiangsu Hengrui Pharmaceuticals, 1288 Haike Road, Shanghai, People’s Republic of China, Email [email protected]: HRS-1780 is a selective non-steroidal mineralocorticoid receptor antagonist developed for the treatment of chronic kidney disease. This study aimed to assess the pharmacokinetics (PK) and safety profiles of HRS-1780 in subjects with renal impairment.Patients and Methods: Eligible participants were enrolled in the healthy (glomerular filtration rate [GFR] of ≥ 90 mL/min), mild (GFR of 60– 89 mL/min), and moderate renal impairment (GFR of 30– 59 mL/min) groups with 9 subjects each and orally received 20 mg HRS-1780. Concentrations of HRS-1780 and its main metabolites were measured in plasma and urine. PK profiles between healthy and renal impairment subjects were compared using analysis of variance.Results: A total of 27 subjects completed the study. HRS-1780 was rapidly absorbed and eliminated, with Tmax of 0.50– 0.52 hour and t1/2 of 2.06– 2.56 hours. Exposure (AUC0-inf) to HRS-1780 was comparable between mildly and moderately renal impaired subjects, while higher, but not significantly than that in healthy subjects. Similar plasma protein binding among different renal function groups suggested a consistent effect of renal function on total and unbound HRS-1780. Renal clearance of HRS-1780 decreased with severity of renal impairment, but renal elimination of HRS-1780 was minimal. Exposure to SX2183-M3 was significantly increased in the moderate renal impairment subjects. Renal impairment did not appear to be associated with an increased risk of adverse events.Conclusion: HRS-1780 PK and safety profiles did not differ significantly between healthy and renal impairment subjects. This supports the drug dose regimen for renal impairment patients in clinical practice.Keywords: mineralocorticoid receptor antagonist, pharmacokinetics, renal impairment, chronic kidney disease