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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.

Authors+Show Affiliations

Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.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.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.

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 -