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. 2023 Sep;29(9):1174-1181.
doi: 10.1016/j.cmi.2023.05.018. Epub 2023 May 20.

A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients

Patrick O Hanafin  1 , Andrea Kwa  2 , Alexandre P Zavascki  3 , Ana Maria Sandri  4 , Marc H Scheetz  5 , Christine J Kubin  6 , Jayesh Shah  7 , Benjamin P Z Cherng  8 , Michael T Yin  7 , Jiping Wang  9 , Lu Wang  9 , David P Calfee  10 , Maureen Bolon  11 , Jason M Pogue  12 , Anthony W Purcell  13 , Roger L Nation  14 , Jian Li  9 , Keith S Kaye  15 , Gauri G Rao  16
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Free article

A population pharmacokinetic model of polymyxin B based on prospective clinical data to inform dosing in hospitalized patients

Patrick O Hanafin et al. Clin Microbiol Infect. 2023 Sep.
Free article

Abstract

Objectives: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients.

Methods: Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA).

Results: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected Cmax, but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower.

Discussion: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated.

Keywords: Clinical; Model; Pharmacokinetics; Polymyxin B; Population.

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