Skip to main content
SpringerLink
Log in

Population Pharmacokinetics of Haloperidol Using Routine Clinical Pharmacokinetic Data in Japanese Patients

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Objective

To clarify the observed variability of haloperidol disposition in patients with psychiatric disorders.

Design

Retrospective population pharmacokinetic study.

Participants

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 • 0.814AGE≥55 • (DOSE/200)0-236 • 1.32ANTIEP and Vd = 34.4 • TBW • 0.336 AGE≥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 (μg/kg/day), ANTIEP = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin or carbamazepine) and 0 otherwise, AGE≥55 = 1 for patient aged 55 years or over and 0 otherwise, and AGE≥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 anti-parkinsonian 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.

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Table III
Table IV
Fig. 1

Similar content being viewed by others

References

  1. Magliozzi JR, Hollister LE, Arnold KV, et al. Relationship of serum haloperidol levels to clinical response in schizophrenic patients. Am J Psychiatry 1981; 138: 365–7

    PubMed  CAS  Google Scholar 

  2. Forsman A, Folsch G, Larsson M, et al. On the metabolism of haloperidol in man. Curr Ther Res 1977; 21: 606–17

    CAS  Google Scholar 

  3. Tsang MW, Shader RI, Greenblatt DJ. Metabolism of haloperidol: clinical implications and unanswered questions. J Clin Psychopharmacol 1994; 14: 159–62

    PubMed  CAS  Google Scholar 

  4. Soudijn W, Wijngaarden I, Allewijn F. Distribution, excretion and metabolism of neuroleptics of the butyrophenone type. Eur J Pharmacol 1967; 1: 47–57

    Article  PubMed  CAS  Google Scholar 

  5. Gorrod JW, Fang J. On the metabolism of haloperidol. Xenobiotica 1993; 23: 495–508

    Article  PubMed  CAS  Google Scholar 

  6. Volavka J, Cooper TB. Review of haloperidol blood levels and clinical response: looking through the window. J Clin Psychopharmacol 1987; 7: 25–30

    Article  PubMed  CAS  Google Scholar 

  7. De Oliveira IR, de Sena EP, Pereira ELA, et al. Haloperidol blood levels and clinical outcome: a meta-analysis of studies relevant to testing the therapeutic window hypothesis. J Clin Pharm Ther 1996; 21: 229–36

    Article  PubMed  Google Scholar 

  8. Ulrich S, Wurthmann C, Brosz M, et al. The relationship between serum concentration and therapeutic effect of haloperidol in patients with acute schizophrenia. Clin Pharmacokinet 1998; 34: 227–63

    Article  PubMed  CAS  Google Scholar 

  9. Froemming JS, Lam YWF, Jann MW, et al. Pharmacokinetics of haloperidol. Clin Pharmacokinet 1989; 17: 396–423

    Article  PubMed  CAS  Google Scholar 

  10. ZumBrunnen TL, Jann MW. Drug interactions with antipsychotic agents: incidence and therapeutic implications. CNS Drugs 1998; 9: 381–401

    Article  CAS  Google Scholar 

  11. Beal SL, Sheiner LB, editors. NONMEM user’s guide. San Francisco (CA): NONMEM Project Group, University of California at San Francisco, 1992

    Google Scholar 

  12. Kamisada M, Oguchi E, Yagi G. Basic evaluation of enzyme immunoassay for haloperidol level and its clinical application. J Clin Ther Med 1988; 4: 639–45

    Google Scholar 

  13. Sheiner LB, Beal SL. Some suggestions for measuring predictive performance. J Pharmacokinet Biopharm 1981; 9: 503–12

    PubMed  CAS  Google Scholar 

  14. Holley FO, Magliozzi JR, Stanski DR, et al. Haloperidol kinetics after oral and intravenous doses. Clin Pharmacol Ther 1983; 33: 477–84

    Article  PubMed  CAS  Google Scholar 

  15. Cheng YF, Paalzow LK, Bondesson U, et al. Pharmacokinetics of haloperidol in psychotic patients. Psychopharmacology 1987; 91: 410–4

    Article  PubMed  CAS  Google Scholar 

  16. Midha KK, Chakraborty BS, Ganes DA, et al. Intersubject variation in the pharmacokinetics of haloperidol and reduced haloperidol. Psychopharmacology 1989; 9: 98–104

    Article  CAS  Google Scholar 

  17. Fang J, Baker GB, Silverstone PH, et al. Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol 1996; 17: 227–33

    Article  Google Scholar 

  18. Pan LP, Wijnant P, De Vriendt C, et al. Characterization of the cytochrome P-450 isoenzymes involved in the in vitro N-dealkylation of haloperidol. Br J Clin Pharmacol 1997; 44: 557–64

    Article  PubMed  CAS  Google Scholar 

  19. Spina E, Pisani F, Perucca E. Clinically significant pharmacokinetic drug interactions with carbamazepine: an update. Clin Pharmacokinet 1996; 31: 198–214

    Article  PubMed  CAS  Google Scholar 

  20. Jann MW, Ereshefsky L, Saklad SR, et al. Effects of carbamazepine on plasma haloperidol levels. J Clin Psychopharmacol 1985; 5: 106–9

    Article  PubMed  CAS  Google Scholar 

  21. Arana GW, Goff DC, Friedman H, et al. Does carbamazepine induced reduction of plasma haloperidol levels worsen psychotic symptoms? Am J Psychiatry 1986; 143: 650–1

    PubMed  CAS  Google Scholar 

  22. Kidron R, Averbuch I, Klein E, et al. Carbamazepine induced reduction in blood levels of haloperidol in chronic schizophrenia. Biol Psychiatry 1985; 20: 199–228

    Article  Google Scholar 

  23. Hirokane G, Someya T, Takahashi S, et al. Interindividual variation of plasma haloperidol concentrations and the impact of concomitant medications: the analysis if therapeutic drug monitoring data. Ther Drug Monit 1999; 21: 82–6

    Article  PubMed  CAS  Google Scholar 

  24. Linnoila M, Viukari M, Vaisanen K, et al. Effect of anticonvulsants on plasma haloperidol and thioridazine levels. Am J Psychiatry 1980; 137: 819–21

    PubMed  CAS  Google Scholar 

  25. Anderson GA. A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 1998; 32: 554–63

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by a Grant-in-Aid from the Nakatomi Foundation (E.Y.) and a Grant-in-Aid from the Japan Research Foundation for Clinical Pharmacology (E.Y.).

Author information

Authors and Affiliations

  1. Laboratory of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, 812-8582, Japan

    Eiji Yukawa, Tsuyoshi Hokazono, Shigehiro Ohdo & Shun Higuchi

  2. Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-Ku, Fukuoka, Japan

    Miho Yukawa & Yoshinobu Goto

  3. Central Laboratory CRC Inc, Higashi-Ku, Fukuoka, Japan

    Ritsuko Ichimaru, Takako Maki, Kanemitsu Matsunaga & Motoaki Anai

Authors
  1. Eiji Yukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsuyoshi Hokazono
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miho Yukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ritsuko Ichimaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takako Maki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kanemitsu Matsunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shigehiro Ohdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Motoaki Anai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shun Higuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoshinobu Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eiji Yukawa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yukawa, E., Hokazono, T., Yukawa, M. et al. Population Pharmacokinetics of Haloperidol Using Routine Clinical Pharmacokinetic Data in Japanese Patients. Clin Pharmacokinet 41, 153–159 (2002). https://doi.org/10.2165/00003088-200241020-00006

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003088-200241020-00006

Keywords

Search

Navigation