title: Population pharmacokinetics of nefopam in elderly, with or without renal impairment, and its link to treatment response.
abstract: OBJECTIVE
  Nefopam is a nonmorphinic central analgesic, for which no recommendation exists concerning adaptation of regimen in aged patients with or without renal impairment. The objective was to describe the pharmacology of nefopam in aged patients to obtain guidelines for practical use.
  
  
  METHODS
  Elderly patients (n = 48), 65-99 years old, with severe or moderate renal impairment or with normal renal function, were recruited. Nefopam (20 mg) was administered as a 30 min infusion postoperatively. Simultaneously, a 1 min intravenous infusion of iohexol was performed, in order to calculate the glomerular filtration rate. Blood samples were drawn to determine nefopam, desmethyl-nefopam and iohexol plasma concentrations. Nefopam and desmethyl-nefopam concentrations were analysed using a nonlinear mixed-effects modelling approach with Monolix version 4.1.3. The association between pharmacokinetic parameters and treatment response was assessed using logistic regression.
  
  
  RESULTS
  A two-compartment open model was selected to describe the pharmacokinetics of nefopam. The typical population estimates (between-subject variability) for clearance, volume of distribution, intercompartmental clearance and peripheral volume were, respectively, 17.3 l h(-1) (53.2%), 114 l (121%), 80.7 l h(-1) (79%) and 208 l (63.6%). Morphine requirement was related to exposure of nefopam. Tachycardia and postoperative nausea and vomiting were best associated with maximal concentration and the rate of increase in nefopam plasma concentration.
  
  
  CONCLUSIONS
  We identified the nefopam pharmacokinetic predictors for morphine requirement and side-effects, such as tachycardia and postoperative nausea and vomiting. In order to maintain morphine sparing and decrease side-effects following a single dose of nefopam (20 mg), simulations suggest an infusion time of >45 min in elderly patients with or without renal impairment.
authors.affiliation: Department of Pharmacology, Reims University Hospital, 51095, Reims Cedex, France.
authors.forename: Zoubir
authors.initials: Z
authors.lastname: Djerada
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fournet-Fayard
authors.forename: Claire
authors.initials: C
authors.lastname: Gozalo
authors.forename: Chantal
authors.initials: C
authors.lastname: Lelarge
authors.forename: Denis
authors.initials: D
authors.lastname: Lamiable
authors.forename: Hervé
authors.initials: H
authors.lastname: Millart
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Malinovsky
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D016015:Logistic Models; D008297:Male; D008954:Models, Biological; D009010:Monte Carlo Method; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects; D009340:Nefopam / Q000493:pharmacokinetics*; D051437:Renal Insufficiency / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D009340:Nefopam; D009020:Morphine
keywords: analgesia; elderly; logistic regression; nefopam; population pharmacokinetics; renal impairment