title: Repeated dosing with donepezil does not affect the safety, tolerability or pharmacokinetics of single-dose thioridazine in young volunteers.
abstract: OBJECTIVE
  To investigate the effects of donepezil at steady state on the safety, tolerability and pharmacokinetics of a single dose of thioridazine, in healthy subjects.
  
  
  METHODS
  An open, two-way, balanced crossover study, in 12 subjects (six men and six women) aged 19-41 years. During both treatment periods, subjects received a single oral dose of 50 mg thioridazine; in one period the thioridazine was given alone, and in the other period it was given together with the last of 15 daily, oral doses of donepezil 5 mg. The 'washout' periods were 1 week when thioridazine was given first, and 2 weeks when thioridazine was given last. Plasma concentrations of thioridazine were measured after each dose, and pharmacokinetic parameters were determined. Interactions were tested by using an equivalence analysis in which thioridazine was the 'Reference' and thioridazine + donepezil the 'Test' regimen. Safety and tolerability were monitored.
  
  
  RESULTS
  Donepezil had no marked effect on the pharmacokinetics of thioridazine, as judged by the equivalence analysis of AUC(0-tn), AUC(0-infinity), t((1/2)) and t(max). C(max) was very similar in the 'Test' and 'Reference' regimens, but the confidence intervals were too wide to confirm equivalence. Donepezil was well tolerated, whereas thioridazine was associated with light-headedness, tiredness and postural hypotension, irrespective of whether or not donepezil was given concurrently.
  
  
  CONCLUSIONS
  Repeated dosing with donepezil, 5 mg daily for 2 weeks, had no significant effect on the safety, tolerability or pharmacokinetics of thioridazine. Thioridazine was poorly tolerated.
authors.affiliation: Eisai Ltd, Hammersmith International Centre, London, UK. miroslav.ravic@antisoma.com
authors.forename: Miroslav
authors.initials: M
authors.lastname: Ravic
authors.forename: Steve
authors.initials: S
authors.lastname: Warrington
authors.forename: Malcolm
authors.initials: M
authors.lastname: Boyce
authors.forename: Kate
authors.initials: K
authors.lastname: Dunn
authors.forename: Atholl
authors.initials: A
authors.lastname: Johnston
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D018592:Cross-Over Studies; D000077265:Donepezil; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010880:Piperidines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D013881:Thioridazine / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D014150:Antipsychotic Agents; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil; D013881:Thioridazine