Pharmacokinetics and pharmacodynamics of polymyxin B and proposed dosing regimens in elderly patients with multi-drug-resistant Gram-negative bacterial infections

Abstract

There are limited data on the pharmacokinetics (PK) and pharmacodynamics (PD) of polymyxin B in the elderly population. The objective of this study was to develop a population PK model of polymyxin B in elderly patients, determine factors that affect its PK parameters, and propose alternative dosing regimens. Critically ill elderly patients (age ≥65 years) who received intravenous polymyxin B for multi-drug-resistant Gram-negative bacterial infections were enrolled. A population PK model was developed using Phoenix NLME software. Monte Carlo simulations were performed to optimize regimens attaining the PK/PD target of AUC24h/MIC >50 and target exposure of 50-100 mg‧h/L. Clinical efficacy and nephrotoxicity of polymyxin B treatment were also assessed. A total of 142 polymyxin B concentrations from 23 patients were available. A two-compartment model with first-order elimination was developed, and albumin was the significant covariate of PK parameters. However, albumin had only a slight effect on polymyxin B exposure. Simulation results indicated that two fixed regimens of 50 mg and 75 mg would be sufficient to reach the PK/PD targets when the minimum inhibitory concentrations was ≤0.5 mg/L. With the exception of 1.25 mg/kg for 58 kg, other weight-based regimens (1.25-1.5 mg/kg for 70 kg and 80 kg; twice daily) may result in at least 40% of predicted AUCss,24h >100 mg‧h/L. In conclusion, fixed maintenance dosing of 50 mg and 75 mg for polymyxin B may maximize efficacy while balancing nephrotoxicity concerns for elderly patients.