Jiali Hu1, Jing Zhang2, Yuancheng Chen1, Wang Liang3, Shi Wu3. 1. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China. 2. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China. Electronic address: zhangj_fudan@aliyun.com. 3. Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Abstract
PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (∆Log24h), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid Emax model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect. FINDINGS: PK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. Cmax and AUC0-24h found only -1.46% and -6.72% differences from the values in vivo. Our study found that ∆Log24h, AUBC, and IKR were more correlated with AUC0-24h/MIC and Cmax/MIC than with %T>MIC. According to ∆Log24h, the PK/PD target values of AUC0-24h/MIC, Cmax/MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively. IMPLICATIONS: Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect.
PURPOSE: This study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. METHODS: An anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (∆Log24h), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid Emax model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect. FINDINGS: PK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. Cmax and AUC0-24h found only -1.46% and -6.72% differences from the values in vivo. Our study found that ∆Log24h, AUBC, and IKR were more correlated with AUC0-24h/MIC and Cmax/MIC than with %T>MIC. According to ∆Log24h, the PK/PD target values of AUC0-24h/MIC, Cmax/MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively. IMPLICATIONS: Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect.