In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis

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 (∆Log 24h ), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid E max 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. C max and AUC 0–24h found only –1.46% and –6.72% differences from the values in vivo. Our study found that ∆Log 24h , AUBC, and IKR were more correlated with AUC 0–24h /MIC and C max /MIC than with %T>MIC. According to ∆Log 24h , the PK/PD target values of AUC 0–24h /MIC, C max /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.