title: Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients.
abstract: OBJECTIVE
  In view of the increasing prevalence of morbidly obese patients, the influence of excessive total bodyweight (TBW) on the pharmacokinetics and pharmacodynamics of propofol was characterized in this study using bispectral index (BIS) values as a pharmacodynamic endpoint.
  
  
  METHODS
  A population pharmacokinetic and pharmacodynamic model was developed with the nonlinear mixed-effects modelling software NONMEM VI, on the basis of 491 blood samples from 20 morbidly obese patients (TBW range 98-167 kg) and 725 blood samples from 44 lean patients (TBW range 55-98 kg) from previously published studies. In addition, 2246 BIS values from the 20 morbidly obese patients were available for pharmacodynamic analysis.
  
  
  RESULTS
  In a three-compartment pharmacokinetic model, TBW proved to be the most predictive covariate for clearance from the central compartment (CL) in the 20 morbidly obese patients (CL 2.33 L/min × [TBW/70]^[0.72]). Similar results were obtained when the morbidly obese patients and the 44 lean patients were analysed together (CL 2.22 L/min × [TBW/70]^[0.67]). No covariates were identified for other pharmacokinetic parameters. The depth of anaesthesia in the morbidly obese patients was adequately described by a two-compartment biophase-distribution model with a sigmoid maximum possible effect (E(max)) pharmacodynamic model (concentration at half-maximum effect [EC(50)] 2.12 mg/L) without covariates.
  
  
  CONCLUSIONS
  We developed a pharmacokinetic and pharmacodynamic model of propofol in morbidly obese patients, in which TBW proved to be the major determinant of clearance, using an allometric function with an exponent of 0.72. For the other pharmacokinetic and pharmacodynamic parameters, no covariates could be identified. Trial registration number (clinicaltrials.gov): NCT00395681.
authors.affiliation: Department of Anesthesiology and Intensive Care, St Antonius Hospital, Nieuwegein, the Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: van Kralingen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Diepstraten
authors.forename: Mariska Y M
authors.initials: MY
authors.lastname: Peeters
authors.forename: Vera H M
authors.initials: VH
authors.lastname: Deneer
authors.forename: Bert
authors.initials: B
authors.lastname: van Ramshorst
authors.forename: René J
authors.initials: RJ
authors.lastname: Wiezer
authors.forename: Eric P A
authors.initials: EP
authors.lastname: van Dongen
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Catherijne A J
authors.initials: CA
authors.lastname: Knibbe
mesh_terms: D018686:Anesthetics, Intravenous / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015992:Body Mass Index; D001835:Body Weight; D056805:Consciousness Monitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009767:Obesity, Morbid / Q000378:metabolism*; D015742:Propofol / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D015742:Propofol