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

Patrick O Hanafin; Andrea Kwa; Alexandre P Zavascki; Ana Maria Sandri; Marc H Scheetz; Christine J Kubin; Jayesh Shah; Benjamin P Z Cherng; Michael T Yin; Jiping Wang; Lu Wang; David P Calfee; Maureen Bolon; Jason M Pogue; Anthony W Purcell; Roger L Nation; Jian Li; Keith S Kaye; Gauri G Rao

doi:10.1016/j.cmi.2023.05.018

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

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

Authors

Patrick O Hanafin¹, Andrea Kwa², Alexandre P Zavascki³, Ana Maria Sandri⁴, Marc H Scheetz⁵, Christine J Kubin⁶, Jayesh Shah⁷, Benjamin P Z Cherng⁸, Michael T Yin⁷, Jiping Wang⁹, Lu Wang⁹, David P Calfee¹⁰, Maureen Bolon¹¹, Jason M Pogue¹², Anthony W Purcell¹³, Roger L Nation¹⁴, Jian Li⁹, Keith S Kaye¹⁵, Gauri G Rao¹⁶

Affiliations

¹ Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Department of Pharmacy, Singapore General Hospital, Singapore, Singapore; Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore.
³ Infectious Diseases Service, Hospital Moinhos de Vento, Porto Alegre, Brazil; Department of Internal Medicine, Medical School, Universidade Federal, Do Rio Grande Do Sul, Porto Alegre, Brazil.
⁴ Infection Control Department, Hospital São Lucas da Pontifícia Universidade Católica Do Rio Grande Do Sul, Porto Alegre, Brazil.
⁵ Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, IL, USA.
⁶ New York-Presbyterian Hospital/Columbia University Irving Medical Center, New York, NY, USA.
⁷ Division of Infectious Diseases, Department of Internal Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁸ Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore.
⁹ Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
¹⁰ Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
¹¹ Department of Healthcare Epidemiology and Infection Prevention, Northwestern Memorial Hospital, Chicago, IL, USA; Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹² Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA.
¹³ Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
¹⁴ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
¹⁵ Division of Allergy, Immunology and Infectious Diseases, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA. Electronic address: kk1116@rwjms.rutgers.edu.
¹⁶ Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: gaurirao@live.unc.edu.

PMID: 37217076
DOI: 10.1016/j.cmi.2023.05.018

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 C_max, 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.

MeSH terms

Anti-Bacterial Agents
Chromatography, Liquid
Creatinine
Critical Illness
Hemodiafiltration* / methods
Humans
Microbial Sensitivity Tests
Polymyxin B* / therapeutic use
Prospective Studies
Tandem Mass Spectrometry

Substances

Polymyxin B
Anti-Bacterial Agents
Creatinine