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In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis.
Clin Ther. 2017 Apr; 39(4):828-836.CT

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.

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Authors+Show Affiliations

Hu J
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.
Zhang J
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.
Chen Y
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.
Liang W
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
Wu S
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.

MeSH

AnaerobiosisAnti-Bacterial AgentsArea Under CurveBacterial InfectionsBacteroides fragilisHumansMicrobial Sensitivity TestsModels, BiologicalOrnidazole

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28363695

Citation

Hu, Jiali, et al. "In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides Fragilis." Clinical Therapeutics, vol. 39, no. 4, 2017, pp. 828-836.
Hu J, Zhang J, Chen Y, et al. In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis. Clin Ther. 2017;39(4):828-836.
Hu, J., Zhang, J., Chen, Y., Liang, W., & Wu, S. (2017). In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis. Clinical Therapeutics, 39(4), 828-836. https://doi.org/10.1016/j.clinthera.2017.03.003
Hu J, et al. In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides Fragilis. Clin Ther. 2017;39(4):828-836. PubMed PMID: 28363695.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis. AU - Hu,Jiali, AU - Zhang,Jing, AU - Chen,Yuancheng, AU - Liang,Wang, AU - Wu,Shi, Y1 - 2017/03/28/ PY - 2017/01/07/received PY - 2017/03/01/revised PY - 2017/03/02/accepted PY - 2017/4/2/pubmed PY - 2017/10/19/medline PY - 2017/4/2/entrez KW - PK/PD target value KW - anaerobe KW - dynamic pharmacokinetic/pharmacodynamic model KW - in vitro KW - levornidazole SP - 828 EP - 836 JF - Clinical therapeutics JO - Clin Ther VL - 39 IS - 4 N2 - 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. SN - 1879-114X UR - https://www.unboundmedicine.com/medline/citation/28363695/In_Vitro_Anaerobic_Pharmacokinetic/Pharmacodynamic_Model_to_Simulate_the_Bactericidal_Activity_of_Levornidazole_Against_Bacteroides_fragilis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0149-2918(17)30177-7 DB - PRIME DP - Unbound Medicine ER -