title: In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis.
abstract: OBJECTIVE
  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 Emaxmodel of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect.
  
  
  RESULTS
  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. Cmaxand AUC0-24hfound 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.
  
  
  CONCLUSIONS
  Our findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect.
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.
authors.forename: Yuancheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Liang
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Wu
mesh_terms: D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001424:Bacterial Infections / Q000188:drug therapy; D001441:Bacteroides fragilis / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D009950:Ornidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D009950:Ornidazole
keywords: PK/PD target value; anaerobe; dynamic pharmacokinetic/pharmacodynamic model; in vitro; levornidazole