The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function

Abstract

Aims: To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone.

Methods: Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child-Pugh A or B) were enrolled into an open-label, multicentre, multiple-dose study. The subjects with chronic, stable hepatic impairment and the matched control subjects received ziprasidone 40 mg day(-1), given orally with food, as two divided daily doses for 4 days and a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 5. Liver function was evaluated quantitatively using antipyrine.

Results: On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no statistically significant differences in the Cmax or tmax for ziprasidone between the two groups. The mean AUC(0,12 h) for ziprasidone was statistically significantly greater in the hepatically impaired subjects compared with the normal subjects (590 ng ml(-1) h vs. 467 ng ml(-1) h, P = 0. 042). However, the AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the matched control group. The ziprasidone lambda(z) in the subjects with normal hepatic function was statistically significantly greater than that in the hepatically impaired subjects (P<0.001). There was no correlation between antipyrine lambda(z) and ziprasidone lambda(z) in the subjects with normal hepatic function or in those with hepatic impairment.

Conclusions: The findings of this study indicate that mild to moderate hepatic impairment does not result in clinically significant alteration of ziprasidone pharmacokinetics.

Figures

Figure 1

Mean serum ziprasidone concentrations on day 1 in subjects with normal (----, n = 13) or impaired (Child-Pugh A cirrhosis (….., n = 7), Child-Pugh B cirrhosis (–––, n =6) and Child-Pugh A or B cirrhosis (-·-·, n =13) hepatic function.

Figure 2

Mean serum ziprasidone concentrations on day 5 in subjects with normal (----, n =13) or impaired (Child-Pugh A cirrhosis (….., n =7), Child-Pugh B cirrhosis (–––, n =6) and Child-Pugh A or B cirrhosis (-·-·, n =13) hepatic function.

Figure 3

Individual AUC(0,12 h) values on day 5 in subjects with normal or impaired hepatic function.

Figure 4

Comparison of individual antipyrine λz at screening with ziprasidone λz on day 5 in subjects with normal (▪) or impaired (Child-Pugh A (□), Child-Pugh B (○) cirrhosis) hepatic function.