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

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_cF 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_cF 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_cF 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_cF 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.