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 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).