Ziprasidone ketoconazole

Cardiovascular side effects. Ziprasidone produced a mean QTc prolongation of 21 ms at maximal blood levels achieved with typical therapeutic doses. However, in all clinical trials, the rate of QTc intervals greater than 500 ms (considered a threshold for arrhythmia risk) did not differ from the rate associated with placebo (<0.1%). The QTc effect of ziprasidone is larger than that of other atypical antipsychotics but smaller than that of thioridazine. Blood levels of ziprasidone increased about 40% when ketoconazole (a metabolic inhibitor) was coadministered, and no change in QTc duration was detected. 

Drugs that inhibit CYP 3A4 reduce metabolism of ziprasidone concurrent treatment with ketoconazole increased blood levels of ziprasidone by approximately 40%. Carbamazepine (and possibly other enzyme inducers) may decrease ziprasidone levels by approximately 35%. Effects of ziprasidone on metabolism of other drugs have not been reported. 

Pfizer, the marketing authorization holder of ziprasidone, has promoted several pharmacokinetic studies. Oral contraceptives (ethinylestradiol 30 pg/day plus levonorgestrel 150 pg/day) (34), lithium 900 mg/day (35), ketoconazole 400 mg/day (36), and carbamazepine (100-400 mg/day)... 

Ziprasidone is oxidatively metabolized by CYP3A4, but it does not inhibit CYP3A4 or other isoenzymes at clinically relevant concentrations. The effect of ketoconazole 400 mg qds for 6 days on the single-dose pharmacokinetics of ziprasidone 40 mg has been evaluated in an open, placebo-controlled, crossover study in healthy volunteers... 

Ketoconazole caused a modest increase in the mean AUC (33%) and the mean Cmax (34%) of ziprasidone. This effect was not considered clinically relevant and suggests that other inhibitors of CYP3A4 are unlikely to affect the pharmacokinetics of ziprasidone significantly. Most of the reported adverse events were mild. The adverse events that were most commonly reported in subjects who took the drugs concomitantly were dizziness, weakness, and somnolence. There were no treatment-related laboratory abnormalities or abnormal vital signs during the study and at the 6-day follow-up evaluation. 

Miceli JJ, Smith M, Robarge L, Morse T, Laurent A. The effects of ketoconazole on ziprasidone pharmacokinetics—a placebo-controlled crossover study in healthy volunteers. Br J Clin Pharmacol 2000 49(Suppl. 1) 71S-6S. 

Clinically important, potentially hazardous interactions with amiodarone, azithromycin, bepredil, bosentan, bretylium, cisapride, clarithromycin, disopyramide, erythromycin, erythromycin fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nefazodone, nilotinib, paroxetine, pimozide, probucol, procainamide, quinidine, quinine, ritonavir, saquinavir, sertraline, sotalol, SSRIs, terfenadine, troleandomycin, voriconazole, zileuton, ziprasidone... 

Clinically important, potentially hazardous interactions with cyclosporine, diltiazem, dofetilide, erythromycin, grapefruit, ketoconazole, quinidine, ritonavir, simvastatin, sotalol, thioridazine, verapamil, ziprasidone... 

A study with the potent CYP 3 A4 inhibitor ketoconazole showed minimal effects on ziprasidone single-dose pharmacokinetics, with only a 33% mean increase in the ziprasidone area under the time-versus-concentration curve. " These results are consistent with data suggesting that aldehyde oxidase is the major metabolic pathway for ziprasidone, with only 30% to 35% being metabolized by CYP 3A4. ... 

Ketoconazole moderately increases ziprasidone levels but this is not expected to be clinically relevant... 

In a randomised, placebo-controlled study, 14 healthy subjects were given a 40-mg dose of ziprasidone before and after taking ketoconazole 400 mg daily for 6 days. It was found that ketoconazole increased the AUC and maximum serum levels of ziprasidone by 33% and 34%, respectively. This modest rise in levels probably occurs because ketoconazole inhibits the cytochrome P450 isoenzyme CYP3A4 by which ziprasidone is metabolised. However, it was concluded that the increase is not clinically relevant. No special precautions would therefore seem to be needed on concurrent use. 

---