Luning Zhuang1, Yang He2, Huiming Xia3, Yajun Liu4, Sherwin K B Sy5, Hartmut Derendorf6. 1. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA Division of Pharmacometrics, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 10903, USA. 2. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA. 3. Division of Clinical Pharmacology IV, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 10903, USA. 4. Division of Bioequivalence II, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 10903, USA. 5. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA Post-Graduate Program in Biostatistics, Department of Statistics, Maringa State University, Maringa, PR 87020, Brazil. 6. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA hartmut@ufl.edu.
Abstract
OBJECTIVES: Gentamicin is widely used in end-stage renal disease (ESRD) patients for the treatment of infections. The goal of this study was to find the most reasonable dosing regimen for gentamicin in ESRD patients receiving haemodialysis. METHODS: The in vitro antimicrobial activity of gentamicin was evaluated by static and dynamic time-kill experiments against three bacterial strains of MSSA, MRSA and Pseudomonas aeruginosa. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was established afterwards, allowing the characterization of the antibacterial effect of gentamicin in the human body. The model was utilized to assess dosing regimens of gentamicin in ESRD patients receiving haemodialysis, taking both efficacy and safety into account. RESULTS: The PK/PD model was capable of describing the bacterial response to gentamicin exposure in all three strains. Simulation based on the PK/PD model showed that pre-dialysis and post-dialysis dosing would bring comparable benefit to the ESRD patient regardless of whether the PK/PD target (fCmax/MIC >8-fold) was achieved, while the post-dialysis dosing resulted in a significantly lower trough concentration. The result of simulated dose fractionation demonstrated that both fCmax/MIC and fAUC(0-24)/MIC are strong predictors of drug effectiveness, but the PK/PD model would provide a more precise prediction of antibacterial activity as well as valuable information on dose selection in ESRD patients receiving haemodialysis. CONCLUSIONS: Our study supports the original FDA label with regard to the dosing regimen of gentamicin in ESRD patients, which offers adequate clinical benefit as well as an acceptable safety profile.
OBJECTIVES:Gentamicin is widely used in end-stage renal disease (ESRD) patients for the treatment of infections. The goal of this study was to find the most reasonable dosing regimen for gentamicin in ESRDpatients receiving haemodialysis. METHODS: The in vitro antimicrobial activity of gentamicin was evaluated by static and dynamic time-kill experiments against three bacterial strains of MSSA, MRSA and Pseudomonas aeruginosa. A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was established afterwards, allowing the characterization of the antibacterial effect of gentamicin in the human body. The model was utilized to assess dosing regimens of gentamicin in ESRDpatients receiving haemodialysis, taking both efficacy and safety into account. RESULTS: The PK/PD model was capable of describing the bacterial response to gentamicin exposure in all three strains. Simulation based on the PK/PD model showed that pre-dialysis and post-dialysis dosing would bring comparable benefit to the ESRDpatient regardless of whether the PK/PD target (fCmax/MIC >8-fold) was achieved, while the post-dialysis dosing resulted in a significantly lower trough concentration. The result of simulated dose fractionation demonstrated that both fCmax/MIC and fAUC(0-24)/MIC are strong predictors of drug effectiveness, but the PK/PD model would provide a more precise prediction of antibacterial activity as well as valuable information on dose selection in ESRDpatients receiving haemodialysis. CONCLUSIONS: Our study supports the original FDA label with regard to the dosing regimen of gentamicin in ESRDpatients, which offers adequate clinical benefit as well as an acceptable safety profile.
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