PMID- 37233875 OWN - NLM STAT- MEDLINE DCOM- 20230619 LR - 20231206 IS - 1865-8652 (Electronic) IS - 0741-238X (Print) IS - 0741-238X (Linking) VI - 40 IP - 7 DP - 2023 Jul TI - Safety, Tolerability, and Pharmacokinetics of Kukoamine B in Healthy Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Multiple-Dose Phase I Study. PG - 3186-3198 LID - 10.1007/s12325-023-02521-1 [doi] AB - INTRODUCTION: Kukoamine B (KB) is a novel sepsis therapeutic drug targeting lipopolysaccharide and CpG DNA. This study aims to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple doses of KB in healthy volunteers. METHODS: Healthy volunteers were randomized at a 1:1:1:1 ratio to receive multiple intravenous infusion doses of KB 0.06 mg/kg, 0.12 mg/kg, 0.24 mg/kg or placebo (administered every 8 h per day) for 7 days and subsequently followed up for another 7 days at Peking Union Medical College Hospital. Primary endpoints were adverse events (AEs), and the secondary endpoints were PK parameters of the first administration and the last administration. RESULTS: Data of the 18 health volunteers in KB groups and 6 in the placebo group were pooled and analyzed. AEs occurred in 12 (66.67%) volunteers in the KB groups and 4 (66.67%) volunteers in the placebo group. Treatment-related adverse events (TRAEs) occurred in 8 (44.44%) volunteers in the KB groups and 2 (33.33%) volunteers in the placebo group. Hypertriglyceridemia (4 [22.22%] vs. 2 [33.33%]) and sinus bradycardia (3 [16.67%] vs. 0) were the most common AEs. The mean elimination half-life, clearance, and distribution volume of KB were 3.40-4.88 h, 9.35-13.49 L/h, and 45.74-101.90 L, respectively. The average accumulation ratios of area under the plasma concentration-time curve and maximum plasma concentration were 1.06 and 1.02, respectively. CONCLUSION: Single and multiple intravenous infusions of KB at a dose range of 0.06-0.24 mg/kg are safe and tolerable in healthy volunteers. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02690961. CI - (c) 2023. The Author(s). FAU - Zhao, Qian AU - Zhao Q AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Liu, Hongzhong AU - Liu H AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Wang, Zhenlei AU - Wang Z AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Wang, Teng AU - Wang T AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Cui, Cheng AU - Cui C AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Wang, Huanhuan AU - Wang H AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Li, Lili AU - Li L AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Zhong, Wen AU - Zhong W AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Jiang, Ji AU - Jiang J AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. FAU - Dong, Kai AU - Dong K AD - Clinical Research Center for Innovative Drugs, Tianjin Chasesun Pharmaceutical Co., Ltd, Tianjin, 301700, China. FAU - Chen, Shuai AU - Chen S 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, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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, Beijing, 100730, China. hubeipumch@163.com. AD - Linking Truth Technology, 11F North Tower, Building B, Huatong Plaza, No. 19 Chegongzhuang Xilu, Haidian District, Beijing, 100048, China. hubeipumch@163.com. LA - eng SI - ClinicalTrials.gov/NCT02690961 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 - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20230526 PL - United States TA - Adv Ther JT - Advances in therapy JID - 8611864 RN - 0 (kukoamine B) MH - Humans MH - *Metabolic Clearance Rate MH - Area Under Curve MH - Infusions, Intravenous MH - Healthy Volunteers MH - Double-Blind Method MH - Dose-Response Relationship, Drug PMC - PMC10271881 OTO - NOTNLM OT - Kukoamine B OT - Pharmacokinetics OT - Safety OT - Sepsis OT - Tolerability COIS- Qian Zhao, Hongzhong Liu, Zhenlei Wang, Teng Wang, Cheng Cui, Lili Li, Ji Jiang and Pei Hu declare no conflict of interest. Kai Dong, Shuai Chen and Chunyan Jin are full-time employees of Tianjin Chasesun Pharmaceutical Co., Ltd. EDAT- 2023/05/26 13:09 MHDA- 2023/06/19 13:08 PMCR- 2023/05/26 CRDT- 2023/05/26 11:10 PHST- 2023/02/23 00:00 [received] PHST- 2023/04/11 00:00 [accepted] PHST- 2023/06/19 13:08 [medline] PHST- 2023/05/26 13:09 [pubmed] PHST- 2023/05/26 11:10 [entrez] PHST- 2023/05/26 00:00 [pmc-release] AID - 10.1007/s12325-023-02521-1 [pii] AID - 2521 [pii] AID - 10.1007/s12325-023-02521-1 [doi] PST - ppublish SO - Adv Ther. 2023 Jul;40(7):3186-3198. doi: 10.1007/s12325-023-02521-1. Epub 2023 May 26.