title: Derivation and cross-validation of pharmacokinetic parameters for computer-controlled infusion of lidocaine in pain therapy.
abstract: BACKGROUND
  Lidocaine administered intravenously is efficacious in treating neuropathic pain at doses that do not cause sedation or other side effects. Using a computer-controlled infusion pump (CCIP), it is possible to maintain the plasma lidocaine concentration to allow drug equilibration between the plasma and the site of the drug effect. Pharmacokinetic parameters were derived for CCIP administration of lidocaine in patients with chronic pain.
  
  
  METHODS
  Thirteen patients (mean age 45 yr, mean weight 66 kg) were studied. Eight subjects received a computer-controlled infusion, targeting four increasing lidocaine concentrations (1-7 micrograms.ml-1) for 30 min each, based on published kinetic parameters in which venous samples were obtained infrequently after bolus administration. From the observations in these eight patients, new lidocaine pharmacokinetic parameters were estimated. These were prospectively tested in five additional patients. From the complete data set (13 patients), final structural parameters were estimated using a pooled analysis approach. The interindividual variability was determined with a mixed-effects model, with the structural model parameters fixed at the values obtained from the pooled analysis. Internal cross-validation was used to estimate the residual error in the final pharmacokinetic model.
  
  
  RESULTS
  The lidocaine administration based on the published parameters consistently produced higher concentrations than desired, resulting in acute lidocaine toxicity in most of the first eight patients. The highest measured plasma concentration was 15.3 micrograms.ml-1. The pharmacokinetic parameters estimated from these eight patients differed from the initial estimates and included a central volume one-sixth of the initial estimate. In the subsequent prospective test in five subjects, the new parameters resulted in concentrations evenly distributed around the target concentration. None of the second group of subjects had evidence of acute lidocaine toxicity. The final parameters ( +/- population variability expressed as %CV) were estimated as follows: V1 0.101 +/- 53% 1.kg-1, V2 0.452 +/- 33% 1.kg-1, Cl1 0.0215 +/- 25% 1.kg-1.min-1, and Cl2 0.0589 +/- 35% 1.kg-1.min-1. The median error measured by internal cross-validation was +1.9%, and the median absolute error was 14%.
  
  
  CONCLUSIONS
  Pharmacokinetic parameters for lidocaine were derived and administration was prospectively tested via computer-controlled infusion pumps for patients with chronic neuropathic pain. The estimated parameters performed well when tested prospectively. A second estimation step further refined the parameters and improved performance, as measured using internal cross-validation.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, California, USA.
authors.forename: T W
authors.initials: TW
authors.lastname: Schnider
authors.forename: R
authors.initials: R
authors.lastname: Gaeta
authors.forename: W
authors.initials: W
authors.lastname: Brose
authors.forename: C F
authors.initials: CF
authors.lastname: Minto
authors.forename: K M
authors.initials: KM
authors.lastname: Gregg
authors.forename: S L
authors.initials: SL
authors.lastname: Shafer
mesh_terms: D000328:Adult; D000779:Anesthetics, Local / Q000493:pharmacokinetics*; D003201:Computers; D005260:Female; D006801:Humans; D007260:Infusion Pumps; D008012:Lidocaine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy*
chemical_list: D000779:Anesthetics, Local; D008012:Lidocaine