Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects

Ji-Young Park, Ji Hong Shon, Kyoung Ah Kim, Hyun Ju Jung, Joo Cheol Shim, Young Ran Yoon, In June Cha, Jae Gook Shin

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured by QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55% compared to placebo pretreatment (21.7 ± 11.3 vs 33.5 ± 29.3 ng h/mL). The subjects with CYP2D6*10/*10 genotype showed 81% higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 ± 22.2 vs 50.2 ± 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 ± 11.3 vs 66.7 ± 62.1 ng h/mL; P < 0.05). The CYP2D6*10/*10 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24% and 25%, respectively, but without a statistical significance. In the subjects with both CYP2D6*10/*10 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42% of subjects with wild genotype in the placebo pretreatment (4.7 ± 3.6 vs 2.0 ± 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.

Original languageEnglish
Pages (from-to)135-142
Number of pages8
JournalJournal of Clinical Psychopharmacology
Volume26
Issue number2
DOIs
Publication statusPublished - 2006 Apr 1

Fingerprint

Cytochrome P-450 CYP2D6
Itraconazole
Genetic Polymorphisms
Haloperidol
Healthy Volunteers
Pharmacokinetics
Genotype
Placebos
Psychomotor Agitation
Cytochrome P-450 CYP3A

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. / Park, Ji-Young; Shon, Ji Hong; Kim, Kyoung Ah; Jung, Hyun Ju; Shim, Joo Cheol; Yoon, Young Ran; Cha, In June; Shin, Jae Gook.

In: Journal of Clinical Psychopharmacology, Vol. 26, No. 2, 01.04.2006, p. 135-142.

Research output: Contribution to journalArticle

Park, Ji-Young ; Shon, Ji Hong ; Kim, Kyoung Ah ; Jung, Hyun Ju ; Shim, Joo Cheol ; Yoon, Young Ran ; Cha, In June ; Shin, Jae Gook. / Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects. In: Journal of Clinical Psychopharmacology. 2006 ; Vol. 26, No. 2. pp. 135-142.
@article{7b18f99419e24d559b7fd3b60634a7f2,
title = "Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects",
abstract = "This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured by QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55{\%} compared to placebo pretreatment (21.7 ± 11.3 vs 33.5 ± 29.3 ng h/mL). The subjects with CYP2D6*10/*10 genotype showed 81{\%} higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 ± 22.2 vs 50.2 ± 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 ± 11.3 vs 66.7 ± 62.1 ng h/mL; P < 0.05). The CYP2D6*10/*10 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24{\%} and 25{\%}, respectively, but without a statistical significance. In the subjects with both CYP2D6*10/*10 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42{\%} of subjects with wild genotype in the placebo pretreatment (4.7 ± 3.6 vs 2.0 ± 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.",
author = "Ji-Young Park and Shon, {Ji Hong} and Kim, {Kyoung Ah} and Jung, {Hyun Ju} and Shim, {Joo Cheol} and Yoon, {Young Ran} and Cha, {In June} and Shin, {Jae Gook}",
year = "2006",
month = "4",
day = "1",
doi = "10.1097/01.jcp.0000203199.88581.c3",
language = "English",
volume = "26",
pages = "135--142",
journal = "Journal of Clinical Psychopharmacology",
issn = "0271-0749",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Combined effects of itraconazole and CYP2D6*10 genetic polymorphism on the pharmacokinetics and pharmacodynamics of haloperidol in healthy subjects

AU - Park, Ji-Young

AU - Shon, Ji Hong

AU - Kim, Kyoung Ah

AU - Jung, Hyun Ju

AU - Shim, Joo Cheol

AU - Yoon, Young Ran

AU - Cha, In June

AU - Shin, Jae Gook

PY - 2006/4/1

Y1 - 2006/4/1

N2 - This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured by QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55% compared to placebo pretreatment (21.7 ± 11.3 vs 33.5 ± 29.3 ng h/mL). The subjects with CYP2D6*10/*10 genotype showed 81% higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 ± 22.2 vs 50.2 ± 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 ± 11.3 vs 66.7 ± 62.1 ng h/mL; P < 0.05). The CYP2D6*10/*10 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24% and 25%, respectively, but without a statistical significance. In the subjects with both CYP2D6*10/*10 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42% of subjects with wild genotype in the placebo pretreatment (4.7 ± 3.6 vs 2.0 ± 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.

AB - This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol, a substrate of both CYP2D6 and CYP3A4, in healthy subjects. Nineteen healthy volunteers whose CYP2D6 genotypes were predetermined were enrolled (9 for CYP2D6*1/*1 and 10 for CYP2D6*10/*10). Four subjects (1 for CYP2D6*1/*1 and 3 for CYP2D6*10/*10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured by QTc prolongation and neurologic side effects were evaluated after a single dose of 5 mg haloperidol following a pretreatment of placebo or itraconazole at 200 mg/d for 10 days in a randomized crossover manner. Itraconazole pretreatment increased the mean area under the time-concentration curves (AUCs) of haloperidol by 55% compared to placebo pretreatment (21.7 ± 11.3 vs 33.5 ± 29.3 ng h/mL). The subjects with CYP2D6*10/*10 genotype showed 81% higher AUC compared to that of subjects with CYP2D6*1/*1 genotype (27.6 ± 22.2 vs 50.2 ± 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D6*10/*10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D6*1/*1 genotype (21.7 ± 11.3 vs 66.7 ± 62.1 ng h/mL; P < 0.05). The CYP2D6*10/*10 genotype and itraconazole pretreatment decreased the oral clearance of haloperidol by 24% and 25%, respectively, but without a statistical significance. In the subjects with both CYP2D6*10/*10 genotype and itraconazole pretreatment, however, the oral clearance was significantly decreased to 42% of subjects with wild genotype in the placebo pretreatment (4.7 ± 3.6 vs 2.0 ± 1.9 L/h/kg; P < 0.05). Barnes Akathisia Rating Scale (BARS) of subjects with CYP2D6*10/*10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D6*1/*1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D6*10 genotype and itraconazole pretreatment caused higher value of UKU side effect and BARS scores. The moderate effect of CYP2D6*10 genotype on the pharmacokinetics and pharmacodynamics of haloperidol seems to be augmented by the presence of itraconazole pretreatment.

UR - http://www.scopus.com/inward/record.url?scp=33646693836&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33646693836&partnerID=8YFLogxK

U2 - 10.1097/01.jcp.0000203199.88581.c3

DO - 10.1097/01.jcp.0000203199.88581.c3

M3 - Article

VL - 26

SP - 135

EP - 142

JO - Journal of Clinical Psychopharmacology

JF - Journal of Clinical Psychopharmacology

SN - 0271-0749

IS - 2

ER -