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 70 kg 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 3.5 mg/kg/day regimens of polymyxin B effectively achieved the fAUC/MIC target of 10 (one log10 kill) against Pseudomonas aeruginosa strains with MIC of 1 mg/L or less (PTA,  90.7% or greater), while the dose regimen were ineffective against strains with an MIC of 2 mg/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 MIC of 0.5 mg/L or less with 3 mg/kg/day regimens. However, the PTA decreased dramatically as MICs increased above 1 mg/L (PTA, 56.1% or less). The polymyxin B dosage regimen of 3.5 mg/kg/day and 3 mg/kg/day are sufficient to treat P. aeruginosa infections with an MIC of 1 mg/L or less and K. pneumoniae infections with an MIC of 0.5 mg/L or less, respectively. The current recommended dose (1.5-3 mg/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.

• Authors: You Zheng, Baohua Xu, Shengyang Chen, Maobai Liu, Huiping Huang, Jingting Wang, Xuemei Wu
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 63 Issue 9 Pg. 1036-1044 (09 2023) ISSN: 1552-4604 [Electronic] England
• PMID: 37125471 (Publication Type: Journal Article)
• Copyright: © 2023, The American College of Clinical Pharmacology.

Chemical References

• Polymyxin B
• Anti-Bacterial Agents

Topics

• Humans
• Polymyxin B
• Anti-Bacterial Agents
• Monte Carlo Method
• Critical Illness
• Computer Simulation
• Microbial Sensitivity Tests