Population Pharmacokinetic Modeling Using Polymyxin B Free Plasma Concentrations From Published Reports and Evaluation of Dosage Regimens Based on Monte Carlo Simulation in Critically Ill Patients.

Abstract

A population pharmacokinetic(pop PK) model of polymyxin B was developed using nonlinear mixed-effects (NONMEM) modeling based on free plasma concentrations to determine whether dose adjustment is required in critically ill patients. One thousand pharmacokinetic profiles for virtual patients with a body weight of 70kg were simulated using Monte Carlo simulation at different dose scenarios, and area under the concentration-time curve of free drug (fAUC) was computed. The probability of target attainment (PTA) at each minimum inhibitory concentration (MIC) was calculated using fAUC/MIC as a pharmacokinetic/pharmacodynamic (PK/PD) index. The final population PK model was a 2-compartment model. PTA showed that 3.5mg/kg/day regimens of polymyxin B effectively achieved the fAUC/MIC target of 10 (one log10 kill) against Pseudomonas aeruginosa strains with MICof 1mg/L or less (PTA,90.7% or greater), while the dose regimen were ineffective against strains with an MIC of 2mg/L or greater (PTA, 56.9% or less). For Klebsiella pneumoniae, the fAUC/MIC target of 17.4 (one log10 kill) was achieved in more than 90.4% of cases for MICof 0.5mg/L or less with 3 mg/kg/day regimens. However, the PTA decreased dramatically as MICs increased above 1mg/L (PTA,56.1% or less). The polymyxin B dosage regimen of 3.5mg/kg/day and 3mg/kg/day are sufficient to treat P. aeruginosa infections with an MIC of 1mg/L or less and K. pneumoniae infections with an MIC of 0.5mg/L or less, respectively. The current recommended dose (1.5-3mg/kg/day) of polymyxin B appears inadequate to attain the PK/PD target for therapeutic efficacy against infections caused by P. aeruginosa and K. pneumoniae isolates when MIC is above the values.