Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6)

Background: The use of pimozide is associated with prolongation of the QT i nterval and fatal ventricular arrhythmia. We recently reported 2 fatal case s in patients taking pimozide and clarithromycin and we have shown that cla rithromycin inhibits CYP3A-mediated metabolism of pimozide in vitro, In thi s study, we examined the effect of clarithromycin on pimozide pharmacokinet ics and QT interval changes in a total of 12 healthy subjects (7 men and 5 women), documented as extensive metabolizers or poor metabolizers of CYP2D6 . Methods: In a randomized, double-blind placebo-controlled crossover design, subjects were given a single 6-mg oral dose of pimozide after 5 days of tr eatment with clarithromycin (500 mg twice a day) or a placebo pill. Blood s amples were obtained before and for 96 hows after pimozide administration, and plasma pimozide and clarithromycin concentrations were measured by HPLC , Electrocardiograms for the analysis of the QTc intervals were recorded im mediately before each blood sample. Results: Pimozide significantly lengthened QTc interval in the first 20 hou rs in both the placebo-treated groups (Delta QTc(max) = 13.3 +/- 5.3 ms; P = .003) and clarithromycin-treated groups (Delta QTc(max) = 15.7 +/- 9.5 ms ; P = .005) compared with baseline values. This is consistent with an effec t of the parent drug. Clarithromycin caused a significant increase in the p eak plasma concentration (P = .015), terminal elimination half-life (P = .0 03), and area under the plasma concentration-time curve (P = .024) and a de crease in the clearance (P = .029) of pimozide, Mean QTc(max) observed with in 20 hours of pimozide administration was significantly greater in the cla rithromycin-treated group (23.8 +/- 12.2 ms; P = .0397) than in the placebo -treated group (16.8 +/- 6 ms). There was no significant effect of CYP2D6 o r gender on the pharmacokinetics or pharmacodynamics of pimozide, Conclusions: A single 6-mg oral dose of pimozide resulted in measurable QT interval changes. Clarithromycin inhibited CYP3A-mediated pimozide metaboli sm and the resulting elevation in plasma concentrations may increase the ri sk of pimoxide cardiotoxicity.