title: Gentamicin dosing strategy in patients with end-stage renal disease receiving haemodialysis: evaluation using a semi-mechanistic pharmacokinetic/pharmacodynamic model.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Luning
authors.initials: L
authors.lastname: Zhuang
authors.affiliation: Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: He
authors.affiliation: 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.
authors.forename: Huiming
authors.initials: H
authors.lastname: Xia
authors.affiliation: Division of Bioequivalence II, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 10903, USA.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Sherwin K B
authors.initials: SK
authors.lastname: Sy
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA hartmut@ufl.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Derendorf
mesh_terms: D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001424:Bacterial Infections / Q000209:etiology* / Q000517:prevention & control*; D005839:Gentamicins / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000628:therapy; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D006435:Renal Dialysis / Q000009:adverse effects
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins