title: Abnormal olanzapine toxicokinetic profiles--population pharmacokinetic analysis.
abstract: BACKGROUND
  Olanzapine is widely used in the treatment of schizophrenia and it is becoming more frequently responsible for overdoses. Standard pharmacokinetic models do not fit to the toxic concentration data.
  
  
  OBJECTIVE
  The aim of present study is to investigate the reasons for an abnormal olanzapine plasma concentration time curve in the range of toxic concentrations. Two hypotheses were verified: entering the enterohepatic cycle, and drug deposition and its desorption from activated charcoal used for gastrointestinal decontamination.
  
  
  METHODS
  One-hundred thirty-five plasma concentration data from 21 patients hospitalized for acute olanzapine poisoning were analyzed with the use of the population pharmacokinetic approach. A non-linear mixed-effects modeling approach with Monolix 4.3.1 was employed.
  
  
  RESULTS
  A model assuming gallbladder emptying at irregular intervals was developed. Also, a model that describes desorption of olanzapine from the charcoal surface, in which the dose is divided into two absorbed fractions, was constructed. The analysis has found gastrointestinal decontamination and previous olanzapine treatment, as the significant covariates for toxicokinetic parameters of olanzapine.
  
  
  CONCLUSIONS
  Our study provides interesting models for investigation of toxic concentration of olanzapine, which may also be used as the basis for further model development for other drugs as well. The investigated population was not large enough to reliably confirm any of the proposed models. It would be well worth continuing this study with more substantial data. Also, any additional information about olanzapine metabolite concentration could be vital.
authors.affiliation: Faculty of Pharmacy, Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University in Kraków , Kraków , Poland .
authors.forename: Zofia
authors.initials: Z
authors.lastname: Tylutki
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jawień
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Ciszowski
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wilimowska
authors.forename: Jacek Sein
authors.initials: JS
authors.lastname: Anand
mesh_terms: D065966:Absorption, Physicochemical; D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000506:poisoning; D001569:Benzodiazepines / Q000097:blood / Q000493:pharmacokinetics* / Q000506:poisoning; D002606:Charcoal / Q000627:therapeutic use; D062787:Drug Overdose / Q000097:blood / Q000628:therapy; D004764:Enterohepatic Circulation; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000077152:Olanzapine; D013269:Stochastic Processes; D066007:Toxicokinetics; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002606:Charcoal; D000077152:Olanzapine
keywords: Enterohepatic circulation; Monolix; resorption