title: Maximizing prediction probability PK as an alternative semiparametric approach to estimate the plasma effect-site equilibration rate constant ke0.
abstract: BACKGROUND
  The k(e)(0) value is the first order rate constant determining the equilibration of drugs between plasma or end-tidal concentration and effect-site (e.g., brain) concentration. Parametric and semiparametric approaches have been used for estimating individual k(e)(0) values and describing the drug-response curve. In this study, we introduce a new semiparametric approach calculating k(e)(0) values for isoflurane, sevoflurane, and desflurane by maximizing the prediction probability P(K).
  
  
  METHODS
  Data from 45 patients scheduled for a radical prostatectomy were analyzed. After lumbar epidural catheterization, patients received remifentanil and propofol solely for induction of anesthesia. Thereafter, epidural analgesia was initiated, and isoflurane, sevoflurane, or desflurane (15 patients each) was added to maintain unconsciousness. At least 45 min later, end-tidal concentrations were varied between 0.5 and 2 minimum alveolar anesthetic concentration. We estimated an individual k(e)(0) value for each patient by optimizing the prediction probability P(K) (P(K)-based k(e)(0)) or by minimizing the area within the hysteresis loop (area-based k(e)(0)). Data are mean +/- sd.
  
  
  RESULTS
  Both semiparametric approaches led to comparable k(e)(0) values with 0.18 +/- 0.06 min(-1) (P(K) based) and 0.15 +/- 0.04 min(-1) (area based) for isoflurane and 0.17 +/- 0.08 min(-1) (P(K) based) and 0.16 +/- 0.11 min(-1) (area based) for sevoflurane. k(e)(0) values for desflurane (P(K) based: 0.30 +/- 0.17min(-1); area based: 0.32 +/- 0.25 min(-1)) were significantly higher than for isoflurane and sevoflurane.
  
  
  CONCLUSIONS
  Maximizing the prediction probability P(K) for estimating k(e)(0) seems to be a promising method that researchers could use on an exploratory basis.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn, Germany. richard.ellerkmann@ukb.uni-bonn.d
authors.forename: Richard K
authors.initials: RK
authors.lastname: Ellerkmann
authors.forename: Joergen
authors.initials: J
authors.lastname: Bruhn
authors.forename: Martin
authors.initials: M
authors.lastname: Soehle
authors.forename: Michael
authors.initials: M
authors.lastname: Kehrer
authors.forename: Andreas
authors.initials: A
authors.lastname: Hoeft
authors.forename: Sascha
authors.initials: S
authors.lastname: Kreuer
mesh_terms: D015360:Analgesia, Epidural; D000767:Anesthesia, Epidural; D018685:Anesthetics, Inhalation / Q000097:blood / Q000493:pharmacokinetics*; D018686:Anesthetics, Intravenous; D003243:Consciousness / Q000187:drug effects; D000077335:Desflurane; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D006801:Humans; D007530:Isoflurane / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008297:Male; D008738:Methyl Ethers / Q000493:pharmacokinetics; D008954:Models, Biological; D015233:Models, Statistical; D016343:Monitoring, Intraoperative / Q000379:methods; D010880:Piperidines; D011336:Probability; D015742:Propofol; D011468:Prostatectomy; D000077208:Remifentanil; D015203:Reproducibility of Results; D000077149:Sevoflurane
chemical_list: D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D008738:Methyl Ethers; D010880:Piperidines; D000077149:Sevoflurane; D000077335:Desflurane; D007530:Isoflurane; D000077208:Remifentanil; D015742:Propofol