Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study.
BACKGROUND
Droperidol and ondansetron have previously been found to prolong the QT interval in the treatment of postoperative nausea and vomiting. However, this adverse effect has never been confirmed and compared with both drugs under controlled conditions. The objective was to study the effects of droperidol and ondansetron alone or in combination on QT interval duration in healthy subjects.


METHODS
Sixteen healthy volunteers, eight males and eight females, were enrolled in this prospective, double-blind, randomized, placebo-controlled study. Subjects received 1 mg droperidol, 4 mg ondansetron, 1 mg droperidol plus 4 mg ondansetron, or a placebo, intravenously in a crossover design. Fridericia-corrected QT interval (QTcF) and plasma concentrations were measured repeatedly during 10 h at each study period. The primary endpoint was the maximal placebo time-matched and baseline-subtracted QTcF prolongation (DeltaDeltaQTcF).


RESULTS
Compared with placebo, both droperidol and ondansetron significantly prolonged the QTcF interval. DeltaDeltaQTcF prolongation was 25 +/- 8 ms after droperidol, significantly greater than the 17 +/- 10-ms prolongation with ondansetron (P = 0.014). The combination of droperidol and ondansetron significantly increased the mean maximal DeltaDeltaQTcF by 28 +/- 10 ms. The combination induced greater QTcF prolongation compared with ondansetron alone (P = 0.001), but not with droperidol alone (P = 0.33). There was no significant pharmacokinetic interaction between droperidol and ondansetron.


CONCLUSIONS
Under controlled conditions, both droperidol and ondansetron either alone or in combination induced significant marked QTc interval prolongation. However, the combination of both drugs did not significantly increase QTc prolongation compared with that induced by droperidol alone.
Charbit
Beny
B
Division of Clinical Pharmacology, St-Antoine University Hospital, 184 rue du Faubourg Saint-Antoine, 75571 Paris Cedex 12, France. beny.charbit@sat.aphp.fr
Alvarez
Jean Claude
JC
Dasque
Eric
E
Abe
Emuri
E
Démolis
Jean Louis
JL
Funck-Brentano
Christian
C
D000328:Adult; D000932:Antiemetics / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004329:Droperidol / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008657:Metabolic Clearance Rate; D017294:Ondansetron / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D000932:Antiemetics; D017294:Ondansetron; D004329:Droperidol