title: Population pharmacokinetic modeling and Monte Carlo simulation of varying doses of intravenous metronidazole.
abstract: 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 >or=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 >or=70 against 218 isolates of B. fragilis (MIC range, 0.125-2.0 mg L(-1)). Mean parameter values were CL(non-OH), 3.08 L h(-1); Vc, 35.4 L; K(OH), 0.04 h(-1); CL(OH), 2.78 L h(-1); and V(OH), 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 >or=70) against B. fragilis isolates is >99% when MICs are <2 mg L(-1), irrespective of the dosing interval of 24 h.
authors.affiliation: College of Pharmacy, University of Illinois, Chicago, IL 60612, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Sprandel
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.forename: David W
authors.initials: DW
authors.lastname: Hecht
authors.forename: John C
authors.initials: JC
authors.lastname: Rotschafer
authors.forename: Larry H
authors.initials: LH
authors.lastname: Danziger
authors.forename: Keith A
authors.initials: KA
authors.lastname: Rodvold
mesh_terms: D000283:Administration, Intravesical; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001441:Bacteroides fragilis / Q000187:drug effects*; D001499:Bayes Theorem; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D004360:Drug Therapy, Computer-Assisted / Q000379:methods; D006801:Humans; D008795:Metronidazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D014018:Tissue Distribution
chemical_list: D000890:Anti-Infective Agents; D008795:Metronidazole