Zhi-Wei Huang1, Ji-Cheng Yu2, Jing-Jing Wang2, Yuan-Cheng Chen2, Ju-Fang Wu2, Yi-Jian Chen3, Guo-Ying Cao2, Hai-Jing Yang2, Jin-Jie He2, Jing-Yi Dai2, Ji-Yin Zhang2, Wei Zhang4, Jing Yuan4, Chun-Lei Li4, Feng-Yan Xu5, Kun Wang5, Xiao-Jie Wu6, Jing Zhang7. 1. Phase Ⅰ Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. 2. Phase Ⅰ Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China. 3. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. 4. CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co, Ltd, Shijiazhuang, China. 5. Shanghai Qiangshi Information Technology Co, Ltd, Shanghai, China. 6. Phase Ⅰ Clinical Research Center, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: wuxiaojie@fudan.edu.cn. 7. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: zhangj_fudan@aliyun.com.
Abstract
PURPOSE: Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. METHODS: PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0-24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. FINDINGS: The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. IMPLICATIONS: PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.
PURPOSE: Amphotericin B colloidal dispersion (ABCD) is a less toxic formulation of amphotericin B for the treatment of invasive fungal infections. The pharmacokinetic (PK) profile and safety of a generic ABCD were investigated after a single dose (0.5 to 1.5 mg/kg) administered as an intravenous infusion in 30 healthy Chinese subjects. METHODS: PK data from healthy Chinese male subjects were applied for developing a population PK model to predict the PK profiles of standard doses (3 or 4 mg/kg) in patients. A 5000-time Monte Carlo simulation of AUC0-24/MIC target was implemented to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) under standard doses. FINDINGS: The PK profiles of intravenous administration of ABCD were best described by a 3-compartmental model with a time-varying clearance and a dose-dependent volume of distribution in the peripheral compartment. PK/pharmacodynamic (PK/PD) analysis revealed that 3 or 4 mg/kg ABCD once a day resulted in favorable CRF (>98%) with 2-log reduction of Candida albicans. A high PTA (>90%) was achieved at MIC ≤2 mg/L for the dosing regimen of ABCD 3 mg/kg and 4 mg/kg for MIC ≤4 mg/L. IMPLICATIONS: PK/PD analysis indicated that a favorable efficacy of ABCD could be reached at a dose of 3 or 4 mg/kg once daily for 14 to 28 days to treat invasive fungal infections caused by C albicans. ClinicalTrials.gov identifier: NCT03577509.