Coadministration of sertraline with cisapride or pimozide: an open-label, nonrandomized examination of pharmacokinetics and corrected QT intervals in healthy adult volunteers.
BACKGROUND
Sertraline hydrochloride is a selective serotonin reuptake inhibitor with demonstrated efficacy and safety for the treatment of the following disorders: major depressive, obsessive-compulsive, panic, premenstrual dysphoric, social anxiety, and posttraumatic stress. Although sertraline is unlikely to cause clinically significant inhibition of cytochrome P450 (CYP) 3A4 substrates, even modest concentration increases for narrow therapeutic index drugs, such as pimozide or cisapride, are potentially important.


OBJECTIVE
The goal of this study was to determine whether there is a pharmacokinetic interaction, as shown by plasma concentrations and electrocardiographic evidence of QTc intervals, between sertraline 200 mg QD and cisapride 10 mg QID, and between sertraline 200 mg QD and pimozide (single 2-mg dose).


METHODS
Patients in group A were administered cisapride on days 1 and 2 (10 mg QID), day 3 (10 mg/d), days 25 through 29 (10 mg QID), and day 30 (10 mg/d). Sertraline was administered on days 4 through 29 at a starting dose of 50 mg/d, which was titrated upward in 50-mg increments every third day to a maximum of 200 mg/d. Patients in group B were treated with 2 mg of pimozide on days 1 and 39. Sertraline was administered on days 18 through 46 at a starting dose of 50 mg/d, which was titrated upward in 50-mg increments every third day to a maximum of 200 mg/d.


RESULTS
There were 9 males and 6 females in group A (sertraline + cisapride) (mean age, 34.4 years for males, 41.7 years for females; mean weight, 78.7 kg for males, 66.6 kg for females; 14 Hispanic, 1 white), and 8 males and 7 females in group B (sertraline + pimozide) (mean age, 26.1 years for males, 33.4 years for females; mean weight, 70.8 kg for males, 61.4 kg for females; 15 Hispanic). Coadministration of sertraline and cisapride resulted in statistically significant reductions of 29% and 36% in cisapride C(max) and AUC from time 0 to 6 hours, respectively, compared with cisapride alone. Coadministration of sertraline and pimozide resulted in statistically significant increases of 35% and 37% in pimozide Cmax and AUC(0-infinity), respectively, compared with pimozide alone. No subject exhibited a prolongation of the QTc interval > or =15% with coadministration of sertraline and cisapride, or sertraline and pimozide.


CONCLUSIONS
This study found that coadministration of sertraline with cisapride resulted in decreases in cisapride concentrations, and no significant effects on QTc intervals. Coadministration of sertraline 200 mg/d and a single dose of pimozide 2 mg produced significant increases in pimozide concentrations but no prolongation of the QTc interval > or =15%. This opposite effect for pimozide compared with cisapride, as well as other previously tested CYP3A4 substrates, suggests that there are mechanisms other than CYP3A4 involved in the sertraline-pimozide interaction.
Alderman
Jeffrey
J
Pfizer Inc., New York, NY 10017, USA. jeffrey.a.alderman@pfizer.com
D000328:Adult; D020117:Cisapride / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D010868:Pimozide / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D020280:Sertraline / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
D020117:Cisapride; D018492:Dopamine Antagonists; D010868:Pimozide; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline