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

This study was to evaluate the combined effects of the CYP3A4 inhibitor itraconazole and the CYP2D610 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 CYP2D61/1 and 10 for CYP2D610/10). Four subjects (1 for CYP2D61/1 and 3 for CYP2D610/10) did not complete the study because of adverse events. The pharmacokinetics of haloperidol and its pharmacodynamic effects measured for 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 CYP2D610/10 genotype showed 81% higher AUC compared to that of subjects with CYP2D61/1 genotype (27.6 +/- 22.2 vs 50.2 +/- 47.1 ng h/mL). In the presence of itraconazole, subjects with CYP2D610/10 showed 3-fold higher AUC of haloperidol compared to that of placebo pretreated subjects with CYP2D61/1 genotype (21.7 +/- 11.3 vs 66.7 +/- 62.1 ng h/mL; P < 0.05). The CYP2D610 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 CYP2D610 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 CYP2D610/10 in the presence of itraconazole pretreatment was significantly higher than that of subjects with CYP2D61/1 genotype in the period of placebo pretreatment. Except for this, all other pharmacodynamic estimations did not reach to statistical significance although each CYP2D610 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.