title: Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens.
abstract: BACKGROUND
  Polymyxin B is a last-line therapy for multidrug-resistant gram-negative bacteria. There is a dearth of pharmacokinetic data to guide dosing in critically ill patients.
  
  
  METHODS
  Twenty-four critically ill patients were enrolled and blood/urine samples were collected over a dosing interval at steady state. Polymyxin B concentrations were measured by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic analysis and Monte Carlo simulations were conducted.
  
  
  RESULTS
  Twenty-four patients aged 21-87 years received intravenous polymyxin B (0.45-3.38 mg/kg/day). Two patients were on continuous hemodialysis, and creatinine clearance in the other patients was 10-143 mL/min. Even with very diverse demographics, the total body clearance of polymyxin B when scaled by total body weight (population mean, 0.0276 L/hour/kg) showed remarkably low interindividual variability (32.4% coefficient of variation). Polymyxin B was predominantly nonrenally cleared with median urinary recovery of 4.04%. Polymyxin B total body clearance did not show any relationship with creatinine clearance (r(2) = 0.008), APACHE II score, or age. Median unbound fraction in plasma was 0.42. Monte Carlo simulations revealed the importance of initiating therapeutic regimens with a loading dose.
  
  
  CONCLUSIONS
  Our study showed that doses of intravenous polymyxin B are best scaled by total body weight. Importantly, dosage selection of this drug should not be based on renal function.
authors.affiliation: Infectious Diseases Service, Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Sandri
authors.forename: Cornelia B
authors.initials: CB
authors.lastname: Landersdorfer
authors.forename: Jovan
authors.initials: J
authors.lastname: Jacob
authors.forename: Márcio M
authors.initials: MM
authors.lastname: Boniatti
authors.forename: Micheline G
authors.initials: MG
authors.lastname: Dalarosa
authors.forename: Diego R
authors.initials: DR
authors.lastname: Falci
authors.forename: Tainá F
authors.initials: TF
authors.lastname: Behle
authors.forename: Rosaura C
authors.initials: RC
authors.lastname: Bordinhão
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Roger L
authors.initials: RL
authors.lastname: Nation
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Alexandre P
authors.initials: AP
authors.lastname: Zavascki
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D001774:Blood Chemical Analysis; D001835:Body Weight; D002853:Chromatography, Liquid; D016638:Critical Illness; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011112:Polymyxin B / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D053719:Tandem Mass Spectrometry; D014556:Urine / Q000737:chemistry; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D011112:Polymyxin B
keywords: dose selection; pharmacokinetics; plasma protein binding; polymyxins; urinary recovery