The effect of carbamazepine on the steady state pharmacokinetics of ziprasidone in healthy volunteers

Aims To evaluate the effect of steady-state carbamazepine administration on the steady-state pharmacokinetics of ziprasidone in healthy young adults, in an open, randomised, parallel-group study. Methods Twenty-five subjects were randomized to one of two treatment groups . Group 1 received 20 mg ziprasidone twice daily on days 1 and 2, and a sin gle dose on day 3. A single 100 mg dose of carbamazepine was given once dai ly on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twic e daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg w as also administered twice daily on days 26 and 27 and in the morning only on day 28. Group 2 received the same treatment regimen with carbamazepine r eplaced by placebo. Pharmacokinetic data were obtained on days 3 and 28. Results Nine subjects in group 1 and 10 in group 2 completed all three trea tment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was asso ciated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and C-max values of 36% and 27%, respectively, o n day 28 compared with day 3 (P < 0.03). The mean differences between day 2 8 and day 3 ziprasidone AUC(0,12 h) and C-max values were also statisticall y significantly greater in the carbamazepine group than in the placebo grou p. The mean half-life of ziprasidone decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine, compared with virtually no change in the placebo group. All adverse events were mild or moderate in severity and there were no serious adverse events, or clinically significant changes in ECGs and vital signs throughout the study. Conclusions Induction of CYP3A4 with carbamazepine led to a modest reductio n (<36%) in steady-state exposure to ziprasidone that is believed to be cli nically insignificant.