title: Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study.
abstract: OBJECTIVE
  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.
authors: Hammersmith Medicines Research, Cumberland Avenue, London NW107ES, UK.
authors: Malcolm J
authors: MJ
authors: Boyce
authors: Kathy J
authors: KJ
authors: Baisley
authors: Steven J
authors: SJ
authors: Warrington
mesh_terms: D058888:14-alpha Demethylase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D018592:Cross-Over Studies; D004294:Domperidone / Q000493:pharmacokinetics* / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D004311:Double-Blind Method; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics* / Q000494:pharmacology; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D012737:Sex Factors; D055815:Young Adult
chemical_list: D058888:14-alpha Demethylase Inhibitors; D018492:Dopamine Antagonists; D004294:Domperidone; D007654:Ketoconazole