Pharmacokinetics and QT interval pharmacodynamics of oral haloperidol in poor and extensive metabolizers of CYP2D6.
We studied the pharmacokinetics and QT interval pharmacodynamics of a single 10 mg dose of oral haloperidol in a randomized, double-blind, placebo-controlled, crossover trial of healthy poor (PMs) and extensive (EMs) metabolizers of CYP2D6. There was a statistically significant greater mean QT(c) on haloperidol (421.6+/-20.1 ms) than on placebo (408.4+/-18.5 ms, P=0.0053) occurring 10 h post haloperidol/placebo administration. Men and women had similar ranges of QT(c) changes from placebo. Despite a statistically significant greater mean elimination half-life (19.1+/-3.6 vs 12.9+/-4.0 h, P=0.04) and lower mean apparent oral clearance (12.8+/-4.1 vs 27.0+/-11.3 ml/min/kg, P=0.02) of haloperidol in CYP2D6 PMs than in EMs, this exposure change did not translate into marked QT(c) changes from baseline that could be considered clinically important. Although the magnitude of the mean QT(c) prolongation on haloperidol relative to placebo is relatively small, it may assume significance in the presence of other risk factors for QT prolongation.
Desai
M
M
Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, 1001 W. 10th Street, Indianapolis, IN 46202-2879, USA.
Tanus-Santos
J E
JE
Li
L
L
Gorski
J C
JC
Arefayene
M
M
Liu
Y
Y
Desta
Z
Z
Flockhart
D A
DA
D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D017931:DNA Primers; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D005838:Genotype; D006207:Half-Life; D006220:Haloperidol / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics
D014150:Antipsychotic Agents; D017931:DNA Primers; D019389:Cytochrome P-450 CYP2D6; D006220:Haloperidol