Relationships among duration of infusion, dose, dosing interval, and steady-state plasma concentrations during intermittent intravenous infusions: Studies with metronidazole

Abstract

Relationships among duration of infusion (T), dose, dosing interval (Τ), maximum and minimum plasma drug concentrations at steady state (C_max,ssand C_min,ss, respectively), and the duration of effective plasma concentrations (t_D) during multidose intermittent infusion regimens were studied by computer simulation using metronidazoie as a model drug. Pharmacokinetic parameter values for metronidazole were obtained from the literature and the minimum effective plasma concentration (MEC) was taken as 6.0 Μg/ ml. Increasing the infusion period of the dose reduces C_max,ss, but increases C_min,ss. If intermittent bolus injection of a given dose of drug results in effective plasma concentrations for the entire dosage interval (i.e., C_min,ss,bolus> MEC), then infusion of that dose over any period (T≤Τ) will also result in effective concentrations for the entire dosage interval. However, if the dosage is such that C_min,ss,bolus < MEC, the relationships among duration of infusion, dose, dosage interval, and duration of effective plasma concentrations are complex. Therefore a nomogram was developed to allow selection of dose, dosing interval, and infusion period such that C_max,ss and C_min,ss could be maintained within a desired range.