Population Pharmacokinetics and Limited Sampling Strategy for Therapeutic Drug Monitoring of Polymyxin B in Chinese Patients With Multidrug-Resistant Gram-Negative Bacterial Infections.

Peile Wang,Qiwen Zhang,Tongwen Sun,Min Feng,Xiaojian Zhang,Jing Yang,Zhenfeng Zhu

doi:10.3389/fphar.2020.00829

Abstract

Polymyxin B is used as a last therapeutic option for the treatment of multidrug-resistant Gram-negative bacterial infections. This study aimed to develop a population pharmacokinetic model and limited sampling strategy, a method to estimate the area under the concentration curve (AUC) by using a limited number of samples, to assist therapeutic drug monitoring of polymyxin B in Chinese patients. Population pharmacokinetic analysis was performed using Phoenix® NLME with data obtained from 46 adult patients at steady state. Various demographic variables were investigated as potential covariates for population pharmacokinetic modeling. The limited sampling strategies based on the Bayesian approach and multiple linear regression were validated using the intraclass correlation coefficient and Bland-Altman analysis. As a result, the data was described by a two-compartment population pharmacokinetic model. Through the modeling, creatinine clearance was found to be a statistically significant covariate influencing polymyxin B clearance. The limited sampling strategies showed the two-point model (C0h and C2h) could predict polymyxin B exposure with good linear relativity (r2 > 0.98), and the four-point model (C1h, C1.5h, C4h, and C8h) performed best in predicting polymyxin B AUC (r2 > 0.99). In conclusion, this study successfully developed a population pharmacokinetic model and limited sampling strategies that could be applied in clinical practice to assist in therapeutic drug monitoring of polymyxin B in Chinese patients.

Highlights

Polymyxin B, a polypeptide antibiotic obtained from the fermentation products of Paenibacillus polymyxa, was first used clinically in the 1950s but was largely abandoned in the 1970s due to nephrotoxicity and neurotoxicity
Demographic characteristics, polymyxin B therapy, and laboratory data before polymyxin B therapeutic drug monitoring (TDM) were collected from electronic medical records, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), urea nitrogen, serum creatinine (Scr), serum uric acid, serum proteins, serum albumin, total bilirubin (TBIL), direct bilirubin (DBIL), and creatinine clearance (CrCL)
MDR Acinetobacter baumannii and Klebsiella pneumoniae were the major causative agent of the infections, and 6 patients were infected with two kinds of MDR Gram-negative bacterial

Summary

Introduction

Polymyxin B, a polypeptide antibiotic obtained from the fermentation products of Paenibacillus polymyxa, was first used clinically in the 1950s but was largely abandoned in the 1970s due to nephrotoxicity and neurotoxicity. Despite being used clinically for decades, few pharmacokinetic/ pharmacodynamics (PK/PD) data is available for polymyxin B (Tam et al, 2005; Bergen et al, 2012; Tsuji et al, 2016; Lakota et al, 2018; Landersdorfer et al, 2018). These studies found the area under the concentration-time curve to minimum inhibitory concentration ratio (fAUC: MIC), as the PK/PD index, appeared to be a good efficacy predictor for polymyxin B. It is necessary to assess the population PK of polymyxin B in Chinese patients

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