title: Population pharmacokinetic-pharmacodynamic modeling and dosing simulation of propofol maintenance anesthesia in severely obese adolescents.
abstract: BACKGROUND
  Optimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines.
  
  
  METHODS
  A prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10.
  
  
  RESULTS
  A three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 μg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW.
  
  
  CONCLUSIONS
  This is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.
authors.affiliation: Division of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Chidambaran
authors.affiliation: Division of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Venkatasubramanian
authors.affiliation: Division of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.|Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Sadhasivam
authors.affiliation: Division of Anesthesiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Hope
authors.initials: H
authors.lastname: Esslinger
authors.affiliation: Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Shareen
authors.initials: S
authors.lastname: Cox
authors.affiliation: Department of Clinical Pharmacy, Reinier de Graaf Group, Delft, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Diepstraten
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.|Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Inge
authors.affiliation: Department of Clinical Pharmacy, Reinier de Graaf Group, Delft, the Netherlands.|Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, the Netherlands.
authors.forename: Catherijne A J
authors.initials: CAJ
authors.lastname: Knibbe
authors.affiliation: Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.|Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
mesh_terms: D000293:Adolescent; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D002648:Child; D004305:Dose-Response Relationship, Drug; D054796:Drug Dosage Calculations; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D009765:Obesity / Q000150:complications / Q000601:surgery*; D015742:Propofol / Q000494:pharmacology*; D011446:Prospective Studies
chemical_list: D018686:Anesthetics, Intravenous; D015742:Propofol
keywords: anesthetics i.v.; bariatric; bispectral index; obese; pediatric; pharmacodynamics; pharmacokinetics; propofol; simulation