Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo‐controlled, double‐blind, crossover study

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Domperidone, a dopamine antagonist metabolized mainly by CYP3A, has been used as an anti‐emetic and prokinetic agent by mouth for over 30 years. • Domperidone has a good safety record. However, early studies of high dose intravenous domperidone were associa...

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Bibliographic Details
Published in:British journal of clinical pharmacology 2012-03, Vol.73 (3), p.411-421
Main Authors: Boyce, Malcolm J., Baisley, Kathy J., Warrington, Steven J.
Format: Article
Language:English
Subjects:
14-alpha Demethylase Inhibitors - pharmacokinetics
14-alpha Demethylase Inhibitors - pharmacology
Adolescent
Adult
Analysis of Variance
Area Under Curve
Arrhythmias, Cardiac - chemically induced
Biological and medical sciences
Cardiac dysrhythmias
Cardiology. Vascular system
Cross-Over Studies
domperidone
Domperidone - pharmacokinetics
Domperidone - pharmacology
Dopamine Antagonists - pharmacokinetics
Dopamine Antagonists - pharmacology
Double-Blind Method
drug interaction
Drug Interactions
Drug toxicity and drugs side effects treatment
Electrocardiography - drug effects
Female
General pharmacology
Heart
Heart Rate - drug effects
Humans
ketoconazole
Ketoconazole - pharmacokinetics
Ketoconazole - pharmacology
Long QT Syndrome - chemically induced
Male
Medical sciences
Miscellaneous (drug allergy, mutagens, teratogens...)
Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions
Pharmacology. Drug treatments
Sex Factors
thorough QT
Young Adult
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Summary:WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Domperidone, a dopamine antagonist metabolized mainly by CYP3A, has been used as an anti‐emetic and prokinetic agent by mouth for over 30 years. • Domperidone has a good safety record. However, early studies of high dose intravenous domperidone were associated with QTc prolongation and arrhythmias, including torsade de pointes. • There have been no thorough QTc studies of domperidone. WHAT THIS STUDY ADDS • We assessed the effect on QTc of oral domperidone and ketoconazole, alone and in combination. • •Ketoconazole, a CYP3A inhibitor, tripled domperidone concentrations, whilst domperidone did not affect ketoconazole concentrations. • •Domperidone and ketoconazole, alone and in combination, increased QTc significantly in men, and there was a positive correlation between increased QTc and concentrations of domperidone and ketoconazole in both sexes. • The effect of domperidone alone on QTc was small and not clinically important, but domperidone should not be co‐administered with ketoconazole. AIMS To assess the steady‐state pharmacokinetic and QTc effects of domperidone and ketoconazole, given alone and together. METHODS A randomized, placebo‐controlled, double‐blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18–39 years; mean weight 73.5 kg, range 53.8–98.8 kg; 23 Europid, 1 Afro‐Caribbean) received orally, for 7 days each, placebo, domperidone 10 mg, four doses daily, at 4 h intervals, ketoconazole 200 mg 12‐hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12‐lead ECGs were assessed on day 7, and serial ECGs on day −1 and at follow‐up. Two subjects withdrew before the third treatment period, so data were available for 22–24 subjects. RESULTS Ketoconazole tripled domperidone concentrations at steady‐state. Domperidone, ketoconazole and their combination significantly increased QTcF in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QTcF was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QTc was positively correlated with plasma drug concentrations, in both men and women. ΔQTcF increased by about 2 ms per 10 ng ml–1 rise in domperidone concentration, and per 1 µg ml–1 rise in ketoconazole concentration. CONCLUSIONS Ketoconazole tripled the p
ISSN:0306-5251
1365-2125
DOI:10.1111/j.1365-2125.2011.04093.x