Huanhuan Qi1, Xin Li2, Yuancheng Chen3, Xueyuan Zhang4, Meng Yang5, Cancan Li5, Hao Feng6, Jing Zhang3, Chunlei Li4. 1. CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., No. 226 Huanghe Street, Shijiazhuang, Hebei 050035, China. Electronic address: lchunlei@mail.ecspc.com. 2. Institute of Antibiotics, Huashan Hospital, Fudan University & Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China. 3. Institute of Antibiotics, Huashan Hospital, Fudan University & Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China; Phase I Unit, Huashan Hospital, Fudan University, Shanghai 200040, China. 4. CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd., No. 226 Huanghe Street, Shijiazhuang, Hebei 050035, China. 5. WuXi AppTec (Shanghai) Co., Ltd., Shanghai 200131, China. 6. Value Pharmaceutical Services Co., Ltd., Nanjing 211800, China.
Abstract
OBJECTIVES: We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of a biosimilar generic product of amphotericin B colloidal dispersion (G-ABCD) againstCandida albicans (MIC 1-2 μg/mL) in a rat model of invasive candidiasis (IC) to facilitate its precision administration. METHODS: Single-dose plasma PKs of G-ABCD was studied in a rat IC model following intravenous administration at doses of 0.0625-10 mg/kg. Amphotericin B concentrations were determined and PK parameters were calculated based on the concentrations in plasma. The efficacy of G-ABCD was evaluated after single administration by the log reduction of CFU counts in kidney, liver, spleen and lung. The relationship between G-ABCD PK/PD index and log CFU reduction in kidney was calculated. RESULTS: Following intravenous administration of G-ABCD at doses of 0.0625-10 mg/kg to rats, the maximum plasma concentration (Cmax) was 0.05-0.82 mg/L and the area under the concentration-time curve from 0 to 24 h (AUC0-24) was 0.50-5.29 mg h/L. G-ABCD showed potent antifungal activity against C. albicans C-13 with a maximum log CFU reduction of 2.1 in kidney. The mean AUC0-24/MIC target of G-ABCD against C. albicans was 0.97 for stasis, 1.40 for 1-log kill and 3.34 for 2-log kill, and the mean Cmax/MIC target was 0.063 for stasis, 0.097 for 1-log kill and 0.348 for 2-log kill. CONCLUSIONS: The antifungal effect of G-ABCD was potent and correlated with AUC0-24/MIC and Cmax/MIC in this rat model of IC. The results of this study provide data for optimising G-ABCD dosing regimens and breakpoints for antifungals.
OBJECTIVES: We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of a biosimilar generic product of amphotericin B colloidal dispersion (G-ABCD) againstCandida albicans (MIC 1-2 μg/mL) in a rat model of invasive candidiasis (IC) to facilitate its precision administration. METHODS: Single-dose plasma PKs of G-ABCD was studied in a rat IC model following intravenous administration at doses of 0.0625-10 mg/kg. Amphotericin B concentrations were determined and PK parameters were calculated based on the concentrations in plasma. The efficacy of G-ABCD was evaluated after single administration by the log reduction of CFU counts in kidney, liver, spleen and lung. The relationship between G-ABCD PK/PD index and log CFU reduction in kidney was calculated. RESULTS: Following intravenous administration of G-ABCD at doses of 0.0625-10 mg/kg to rats, the maximum plasma concentration (Cmax) was 0.05-0.82 mg/L and the area under the concentration-time curve from 0 to 24 h (AUC0-24) was 0.50-5.29 mg h/L. G-ABCD showed potent antifungal activity against C. albicans C-13 with a maximum log CFU reduction of 2.1 in kidney. The mean AUC0-24/MIC target of G-ABCD against C. albicans was 0.97 for stasis, 1.40 for 1-log kill and 3.34 for 2-log kill, and the mean Cmax/MIC target was 0.063 for stasis, 0.097 for 1-log kill and 0.348 for 2-log kill. CONCLUSIONS: The antifungal effect of G-ABCD was potent and correlated with AUC0-24/MIC and Cmax/MIC in this rat model of IC. The results of this study provide data for optimising G-ABCD dosing regimens and breakpoints for antifungals.