Population pharmacokinetic modeling and Monte Carlo simulation (MCS) are approaches used to determine probability of target attainment (PTA) of antimicrobial therapy. The objectives of this study were 1) to determine a population pharmacokinetic model (PPM) using metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients, and 2) to determine the probability of attaining the pharmacodynamic target area under the plasma concentration (AUC)/MIC ratio ≥70 against 218 clinical isolates of Bacteroides fragilis using MCS. Eighteen healthy subjects were randomized to 3 dosages of intravenous metronidazole (500 mg every 8 h, 1000 mg day-1, 1500 mg day-1) in an open-label 3-way crossover fashion. Serial blood samples were collected over 25.5 h on the 3rd day of each study period. An additional of 8 critically ill patients received intravenous metronidazole 500 mg every 8 h. Serial blood samples were collected over 8 h after the 2nd day of dosing. Plasma metronidazole and hydroxy-metronidazole concentrations were analyzed using a high-performance liquid chromatographic assay. The 834 plasma concentrations from 62 data sets were simultaneously modeled with Non-Parametric Adaptive Grid population modeling program. A 4-compartment model with a metabolite and zero-order infusion into the central compartment was used. The mean parameter vector and covariance matrix from PPM were inserted into the simulation module of ADAPT II. A 10 000-subject MCS was performed to determine the probability of PTA for a total drug AUC to MIC ratio ≥70 against 218 isolates of B. fragilis (MIC range, 0.125-2.0 mg L-1). Mean parameter values were CLnon-OH, 3.08 L h-1; Vc, 35.4 L; KOH, 0.04 h-1; CLOH, 2.78 L h-1; and VOH, 9.66 L. The regression values of the observed versus predicted concentrations (r2) of metronidazole and hydroxy-metronidazole were 0.972 and 0.980, respectively. The PTA for metronidazole 1500 mg day-1 or 500 mg every 8 h (taken together) and 1000 mg day-1 were 99.9% and 99.8%, respectively, over the reported MIC distribution range. For an MIC of 4 mg L-1, the predicted PTA decreased to 80.0% and 28.5%, respectively. A PPM was determined by comodeling metronidazole and hydroxy-metronidazole concentrations from healthy subjects and critically ill patients. Based on this model, attainment of the target pharmacodynamic parameter (AUC/MIC ratio ≥70) against B. fragilis isolates is >99% when MICs are <2 mg L-1, irrespective of the dosing interval of 24 h.
|Original language||English (US)|
|Number of pages||7|
|Journal||Diagnostic Microbiology and Infectious Disease|
|State||Published - Aug 2006|
Bibliographical noteFunding Information:
This work was funded in part by a research grant from Ortho-McNeil Pharmaceutical (Raritan, NJ). This work was supported in part by the General Clinical Research Center at the University of Illinois at Chicago, which is funded by NIH grant M01-RR-13987. The authors would like to thank the Clinical Research Center staff for help and support of this study.