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Technical Aspect of the Automated Synthesis and Real-Time Kinetic Evaluation of [11C]SNAP-7941
Published on: April 28, 2019
First-in-Human Phase I Trial of HRS-2129, a Selective Nav1.8 Inhibitor: Safety, Tolerability, Pharmacokinetics, and
Jie Huang1,2,3,4, Qian Wu2,3, Saiying Wang5
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, People's Republic of China.
Background:
HRS-2129 is a novel, orally administered, selective Nav1.8 sodium channel blocker under development for pain management. This first-in-human study evaluated its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy subjects.
Methods:
Two randomized, double-blind, placebo-controlled studies were conducted: a single ascending dose (SAD) study (25-600 mg, n=44) and a multiple ascending dose (MAD) study (25 mg BID, 25 mg QD, 75 mg QD, n=23). Safety, PK, and PD (cold/heat pain thresholds and pain tolerance time) were assessed.
Results:
HRS-2129 exhibited favorable tolerability following a single administration (25-600 mg) and repeated dosing at 25 mg BID. No severe or serious adverse events (SAEs) occurred in the SAD study. One SAE (drug rash) led to discontinuation in the 75 mg QD cohort during the MAD phase. Common AEs were mild and included proteinuria, occult blood, and ECG T-wave abnormalities. PK analysis showed rapid absorption, a long half-life supporting once-daily dosing, less than dose-proportional exposure, and moderate accumulation at steady state. Food delayed absorption without affecting overall exposure. PD results showed increased pain tolerance time in the ice-water bath test without clear dose dependency.
Conclusion:
Within the evaluated dose range, HRS-2129 demonstrated a favorable safety profile, predictable PK with low accumulation, and preliminary evidence of analgesic effect. These results support further clinical development for both acute and chronic pain.
Trial Registration:
http://www.chinadrugtrials.org.cn, identifier NCT06619392 and NCT06742840.
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