Population pharmacokinetics of haloperidol using routine clinical pharmacokinetic data in Japanese patients.
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.
Yukawa
Eiji
E
Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-Ku, Fukuoka, Japan. yukawa@shunsan.phar.kyushu-u.ac.jp
Hokazono
Tsuyoshi
T
Yukawa
Miho
M
Ichimaru
Ritsuko
R
Maki
Takako
T
Matsunaga
Kanemitsu
K
Ohdo
Shigehiro
S
Anai
Motoaki
M
Higuchi
Shun
S
Goto
Yoshinobu
Y
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
D000927:Anticonvulsants; D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D006220:Haloperidol