The effects of ketoconazole on ziprasidone pharmacokinetics - a placebo-controlled crossover study in healthy volunteers

Aims To assess the effects of multiple oral doses of ketoconazole on the si ngle-dose pharmacokinetics of oral ziprasidone HCl. Methods This was a 14-day, open-label, randomized, crossover study in 14 he althy subjects aged 18-31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash-out period and 6 days of pl acebo administration. Group 2 received placebo followed by ketoconazole. Si ngle oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared betwe en placebo and ketoconazole administration periods. Results Co-administration of ziprasidone with ketoconazole was associated w ith a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,infin ity) increased by 33%, from 899 ng ml(-1) h with placebo to 1199 ng ml(-1) h with ketoconazole. Mean C-max increased by 31%, from 89 ng ml(-1) to 119 ng ml(-1), respectively. The treatment effect on both of these parameters w as statistically significant (P < 0.02). Most adverse events were of mild i ntensity. There were no serious adverse events, laboratory abnormalities, a bnormal ECGs, or clinically significant alterations in vital signs througho ut the study. Conclusions The concurrent administration of ketoconazole and ziprasidone l ed to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This sug gests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.