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

Abstract

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 single dose on day 3. A single 100 mg dose of carbamazepine was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg was 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 replaced 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 treatment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was associated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3 (P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h) and Cmax values were also statistically significantly greater in the carbamazepine group than in the placebo group. 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 reduction (<36%) in steady-state exposure to ziprasidone that is believed to be clinically insignificant.

Figure 1

Mean serum ziprasidone concentrations in subjects receiving ziprasidone (40 mg day⁻¹) before (day 3) and after (day 28) the administration of placebo or carbamazepine for 21 days. Day 3 group 1 – carbamazepine (•), day 3 group 2 – placebo (○), day 28 group 1 – carbamazepine (▪), day 28 Group 2 – placebo (□).

Figure 2

Mean AUC(0,12 h), C_max and t_½,z on days 3 and 28 in subjects receiving ziprasidone (40 mg day⁻¹) before (day 3) and after (day 28) the administration of placebo or carbamazepine for 21 days. Solid lines (----) represent individual observed values, and dashed lines (▪––––▪) represent geometric (C_max, AUC(0,12 h)) and harmonic (t_1/2) mean values.