Affordable Access

deepdyve-link
Publisher Website

Population Pharmacokinetics of Polymyxin B in Acutely Ill Adult Patients.

Authors
  • Miglis, Cristina1
  • Rhodes, Nathaniel J1
  • Avedissian, Sean N1
  • Kubin, Christine J2
  • Yin, Michael T3
  • Nelson, Brian C4
  • Pai, Manjunath P5
  • Scheetz, Marc H6
  • 1 Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois, USA.
  • 2 Department of Pharmacy and Division of Infectious Diseases, New York-Presbyterian Hospital-Columbia University Irving Medical Center, New York, New York, USA.
  • 3 Division of Infectious Diseases, Columbia University Irving Medical Center, New York, New York, USA.
  • 4 Department of Pharmacy, New York-Presbyterian Hospital-Columbia University Irving Medical Center, New York, New York, USA.
  • 5 University of Michigan, Ann Arbor, Michigan, USA.
  • 6 Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois, USA [email protected]
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Publication Date
Mar 01, 2018
Volume
62
Issue
3
Identifiers
DOI: 10.1128/AAC.01475-17
PMID: 29311071
Source
Medline
Keywords
License
Unknown

Abstract

Polymyxin B (PB) has reemerged as a common treatment against multidrug-resistant Gram-negative pathogens. However, nephrotoxicity remains a significant dose-limiting side effect, and contemporary pharmacokinetic (PK) data are limited. This study sought to evaluate PB exposure differences in various loading and nonloading strategies according to total body weight (TBW) and adjusted body weight (ABW). Patients treated with PB had plasma samples obtained for clinical care and analyzed using liquid chromatography-tandem mass spectrometry. Compartmental PK models with linear and allometric scaling of TBW were explored. Semiparametric Monte Carlo simulation evaluated the total (i.e., protein bound plus unbound) area under the plasma concentration-time curve (AUCtotal) during the first 24 h of therapy and at 96 h posttherapy for each regimen at the 10th, 50th, and 90th percentiles of TBW and ABW in the derivation cohort. Literature-based values of the 24-h total AUC/MIC ratio (AUC/MICtotal) of ≥50 defined efficacy, and literature-based values of the 72- to 96-h AUCtotal of ≥100 μg · h/ml defined toxicity. Fifty-two patients contributed 156 PB plasma samples. A two-compartment model with allometric scaling of TBW produced a comparable fit (Akaike information criterion [AIC] = 376.7) to that achieved with linear scaling (AIC = 378). The regimen of a loading dose of 2.5 mg/kg of body weight plus a fixed dose of 100 mg every 12 h had the highest probability of achieving a 24-h AUC/MICtotal of ≥50 with the lowest probability of toxicity in all groups at 24 h, aside from those with the lowest 10th percentile of body weight. This is the first study to suggest that a weight-based loading and fixed maintenance (i.e., weight-independent) dosing strategy for polymyxin B may maximize efficacy while balancing toxicity concerns for most patients.

Report this publication

Statistics

Seen <100 times