Safety, Tolerability, and Pharmacokinetics of NorUrsodeoxycholic Acid (Shilpa Medicare Limited, India) in Healthy Adults: Results From a Phase I Open-Label Dose-Escalation Study.

NorUrsodeoxycholic acid (norUDCA) is a side-chain-shortened derivative of ursodeoxycholic acid (UDCA) with specific pharmacological properties, including cholehepatic shunting, making it a promising candidate for a range of cholestatic and metabolic liver diseases. This phase I study evaluates the safety, tolerability, and pharmacokinetics of single ascending doses of norUDCA in healthy adults under fasting conditions. In this open-label, dose-escalation study, healthy adults (aged 18-45 years) were enrolled into 3 successive dose escalation cohorts, receiving norUDCA oral tablets of 500 mg (n = 14), 1000 mg (n = 14), and 1500 mg (n = 14) once daily. The primary endpoints were the incidence rate of dose-limiting toxicities (DLTs), assessment of maximum tolerated dose (MTD) after single dose administration, and an establishment of the recommended phase II dose. Secondary endpoints included pharmacokinetic assessments and evaluation of dose proportionality. Following single-dose administration of 500 mg, 1000 mg, and 1500 mg, no DLTs were observed, and the MTD was determined to be 1500 mg/day. Maximum plasma concentration (C _max) and plasma exposure [area under the curve (AUC)] to norUDCA increased dose proportionally from 500 to 1500 mg/day. Median time to achieve maximum plasma concentration (T _max) for norUDCA at 1500 mg/day cohort (3 h) was comparable to 1000 mg/day cohort (3 h) but lower than 500 mg/day cohort (4 h). The half-life was longer in 1500 mg/day (16 h) cohort compared to 500 mg/day (15 h) and 1000 mg/day cohorts (14 h). The 90% confidence interval of the slope estimates for C _max (22.41, 59.70), AUC_0-t (11.71, 61.14), and AUC_0-inf (10.74, 61.86) did not consistently fall within the predefined acceptable limits (79.69, 120.31) for formal dose proportionality criteria. No serious adverse events or deaths occurred in any cohort. One treatment-emergent adverse event was observed (an increase in the white blood cell count), which was not related to the study drug. A single dose of norUDCA is safe and well-tolerated, with favorable plasma pharmacokinetic profiles in healthy subjects. Based on the safety and pharmacokinetic data, the recommended dosage for further clinical trials is 1500 mg/day. Trial Registration: Clinical Trials Registry-India: CTRI/2022/11/047561.