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

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


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • 14-alpha Demethylase Inhibitors / pharmacokinetics*
  • 14-alpha Demethylase Inhibitors / pharmacology
  • Adolescent
  • Adult
  • Analysis of Variance
  • Area Under Curve
  • Arrhythmias, Cardiac / chemically induced
  • Cross-Over Studies
  • Domperidone / pharmacokinetics*
  • Domperidone / pharmacology
  • Dopamine Antagonists / pharmacokinetics*
  • Dopamine Antagonists / pharmacology
  • Double-Blind Method
  • Drug Interactions
  • Electrocardiography / drug effects
  • Female
  • Heart Rate / drug effects*
  • Humans
  • Ketoconazole / pharmacokinetics*
  • Ketoconazole / pharmacology
  • Long QT Syndrome / chemically induced*
  • Male
  • Sex Factors
  • Young Adult


  • 14-alpha Demethylase Inhibitors
  • Dopamine Antagonists
  • Domperidone
  • Ketoconazole