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Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo‐controlled, double‐blind, crossover study
Author(s) -
Boyce Malcolm J.,
Baisley Kathy J.,
Warrington Steven J.
Publication year - 2012
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2011.04093.x
Subject(s) - domperidone , ketoconazole , crossover study , medicine , placebo , pharmacokinetics , pharmacology , qt interval , anesthesia , dopamine , dermatology , antifungal , alternative medicine , pathology
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 QT c prolongation and arrhythmias, including torsade de pointes. • There have been no thorough QT c studies of domperidone. WHAT THIS STUDY ADDS • We assessed the effect on QT c 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 QT c significantly in men, and there was a positive correlation between increased QT c and concentrations of domperidone and ketoconazole in both sexes. • The effect of domperidone alone on QT c was small and not clinically important, but domperidone should not be co‐administered with ketoconazole. AIMS To assess the steady‐state pharmacokinetic and QT c 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 QT c F 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, QT c F was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QT c was positively correlated with plasma drug concentrations, in both men and women. ΔQT c F 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 plasma concentrations of domperidone. Domperidone and ketoconazole increased QT c F in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained.