PMID- 38291280 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240303 IS - 2193-8229 (Print) IS - 2193-6382 (Electronic) IS - 2193-6382 (Linking) VI - 13 IP - 2 DP - 2024 Feb TI - First-in-Human Safety, Tolerability, and Pharmacokinetics of Single-Dose Kukoamine B Mesylate in Healthy Subjects: A Randomized, Double-Blind, Placebo-Controlled Phase I Study. PG - 361-371 LID - 10.1007/s40121-024-00921-6 [doi] AB - INTRODUCTION: Kukoamine B mesylate (KB) is a mesylate chrysamine B targeting lipopolysaccharides and CpG DNA, two potential treatment targets in sepsis. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase I study was conducted from July 2014 to May 2015 to explore the safety, tolerability, and pharmacokinetics of KB in healthy subjects. This study consisted of a pre-phase (four participants; KB at 0.005 mg/kg) and a dose escalation phase (eight participants/dose group, randomized 6:2 to KB or placebo; KB at 0.02, 0.04, 0.08, 0.12, 0.24, and 0.48 mg/kg). The primary endpoint was safety. RESULTS: Fifty-two participants were enrolled, including four in the pre-phase and 48 in the dose escalation phase. Among the 40 participants who received KB, 12 (30.0%) experienced adverse events (AEs), while two (16.7%) experienced AEs among 12 participants who received the placebo. The most common AEs in the KB group were headache (5.0%), influenza (5.0%) and positive white blood cell in urine (5.0%). After the administration of KB, the mean plasma elimination half was around 1.61-4.24 h. The relationship between the KB plasma exposure of KB and the administered dose was not linear. The percentage of cumulative urinary excretion of KB was similar among the different dose groups (21.7-35.2%) and the urinary excretion of KB decreased significantly about 8 h after administration. CONCLUSIONS: Single-dose KB demonstrated favorable safety and tolerability in healthy subjects at the dose level of 0.005-0.48 mg/kg. KB exhibited a non-linear pharmacokinetic profile with a half-life of about 1.61-4.24 h, which mainly distributed in plasma. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02219971. CI - (c) 2024. The Author(s). FAU - Liu, Hongzhong AU - Liu H AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Zhao, Qian AU - Zhao Q AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Yuan, Yuping AU - Yuan Y AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Wang, Zhenlei AU - Wang Z AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Wang, Teng AU - Wang T AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Tian, Wei AU - Tian W AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Zhong, Wen AU - Zhong W AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Jiang, Ji AU - Jiang J AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. FAU - Chen, Shuai AU - Chen S AD - Clinical Research Center for Innovative Drugs, Tianjin Chasesun Pharmaceutical Co., Ltd., Tianjin, 301700, China. FAU - Kong, Kai AU - Kong K AD - Clinical Research Center for Innovative Drugs, Tianjin Chasesun Pharmaceutical Co., Ltd., Tianjin, 301700, China. FAU - Jin, Chunyan AU - Jin C AD - Clinical Research Center for Innovative Drugs, Tianjin Chasesun Pharmaceutical Co., Ltd., Tianjin, 301700, China. FAU - Hu, Pei AU - Hu P AD - Clinical Pharmacology Research Center, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China. hubeipumch@163.com. LA - eng SI - ClinicalTrials.gov/NCT02219971 GR - 2022-PUMCH-B-118/National High Level Hospital Clinical Research Funding/ GR - 2022-PUMCH-A-144/National High Level Hospital Clinical Research Funding/ GR - 2022-PUMCH-B-033/National High Level Hospital Clinical Research Funding/ GR - ZZ19005/Jinqiao Project of Beijing Association of Science and Technology/ GR - 2019DL001/Drug Development and Application of Chinese Pharmacological Society/ PT - Journal Article DEP - 20240130 PL - New Zealand TA - Infect Dis Ther JT - Infectious diseases and therapy JID - 101634499 PMC - PMC10904689 OTO - NOTNLM OT - Kukoamine B OT - Pharmacokinetic OT - Phase I trial OT - Safety COIS- Hongzhong Liu, Qian Zhao, Yuping Yuan, Zhenlei Wang, Teng Wang, Wei Tian, Wen Zhong, Ji Jiang, and Pei Hu declare no conflicts of interest. Shuai Chen, Kai Kong, and Chunyan Jin are full-time employees of Tianjin Chasesun Pharmaceutical Co., Ltd. EDAT- 2024/01/31 00:42 MHDA- 2024/01/31 00:43 PMCR- 2024/01/30 CRDT- 2024/01/30 23:32 PHST- 2023/11/16 00:00 [received] PHST- 2024/01/10 00:00 [accepted] PHST- 2024/01/31 00:43 [medline] PHST- 2024/01/31 00:42 [pubmed] PHST- 2024/01/30 23:32 [entrez] PHST- 2024/01/30 00:00 [pmc-release] AID - 10.1007/s40121-024-00921-6 [pii] AID - 921 [pii] AID - 10.1007/s40121-024-00921-6 [doi] PST - ppublish SO - Infect Dis Ther. 2024 Feb;13(2):361-371. doi: 10.1007/s40121-024-00921-6. Epub 2024 Jan 30.