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Br J Clin Pharmacol. 2012 Mar;73(3):411-21. doi: 10.1111/j.1365-2125.2011.04093.x.

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

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1
Hammersmith Medicines Research, Cumberland Avenue, London NW107ES, UK.

Abstract

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 73.5kg, range 53.8-98.8kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10mg, four doses daily, at 4h intervals, ketoconazole 200mg 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 2ms per 10ngml(-1) rise in domperidone concentration, and per 1µgml(-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.

PMID:
21883386
PMCID:
PMC3370345
DOI:
10.1111/j.1365-2125.2011.04093.x
[Indexed for MEDLINE]
Free PMC Article

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