title: Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.
abstract: OBJECTIVE
  To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders.
  
  
  METHODS
  Retrospective population pharmacokinetic study.
  
  
  METHODS
  218 Japanese patients aged 16 to 82 years who provided 391 serum haloperidol concentrations.
  
  
  METHODS
  Routine clinical pharmacokinetic data gathered from patients receiving haloperidol were analysed to estimate population pharmacokinetic parameters with the nonlinear mixed effects model (NONMEM) computer program.
  
  
  RESULTS
  The final pharmacokinetic model was CL = 42.4 * (TBW/60)(0.655) * 0.814(AGE> or = 55) * (DOSE/200)(0.236) * 1.32(ANTIEP) and Vd = 34.4 * TBW * 0.336( AGE> or = 65), where CL is total body clearance (L/h), Vd is apparent volume of distribution (L), TBW is total bodyweight (kg), DOSE is daily dosage (microg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE > or = 55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE > or = 65 = 1 for patient aged 65 years or over and 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or over showed an 18.6% reduction in clearance, and elderly patients aged 65 years or over showed a 66.4% reduction in apparent volume of distribution. Inclusion of terms for the concomitant administration of haloperidol and antiparkinsonian drugs (amantadine, bromocriptine, biperiden, trihexyphenidyl or mazaticol) or cytochrome P450 (CYP) 2D6 substrates (levomepromazine, perphenazine, thioridazine, amitriptyline or clomipramine) did not significantly improve the estimate of haloperidol clearance.
  
  
  CONCLUSIONS
  Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target haloperidol serum concentrations, thus enabling the clinician to achieve the desired therapeutic effect.
authors.affiliation: Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-Ku, Fukuoka, Japan. yukawa@shunsan.phar.kyushu-u.ac.jp
authors.forename: Eiji
authors.initials: E
authors.lastname: Yukawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hokazono
authors.forename: Miho
authors.initials: M
authors.lastname: Yukawa
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Ichimaru
authors.forename: Takako
authors.initials: T
authors.lastname: Maki
authors.forename: Kanemitsu
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.forename: Motoaki
authors.initials: M
authors.lastname: Anai
authors.forename: Shun
authors.initials: S
authors.lastname: Higuchi
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Goto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants / Q000627:therapeutic use; D000978:Antiparkinson Agents / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D005260:Female; D006220:Haloperidol / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007564:Japan; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D012189:Retrospective Studies
chemical_list: D000927:Anticonvulsants; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D006220:Haloperidol