Aims To assess whether renal impairment in¯uences the pharmacokinetics of ziprasidone, and to determine whether ziprasidone is cleared via haemodialysis. Methods Thirty-nine subjects with varying degrees of renal impairment were enrolled into an open-label, multicentre, multiple-dose study and assigned to four groups according to their renal function: normal (group 1, creatinine clearance >70 ml min x 1 ); mildly impaired (group 2, creatinine clearance 30±60 ml min x 1 ); moderately impaired (group 3, creatinine clearance 10±29 ml min x 1 ), and severely impaired (group 4, requiring haemodialysis three times-a-week). Subjects received ziprasidone 40 mg day x 1 , given orally with food, as two divided daily doses for 7 days and a single 20 mg dose on the morning of day 8. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 8 (haemodialysis day for subjects with severe renal impairment). Additional samples were collected from subjects with severe renal impairment on day 7 (nonhaemodialysis day). Results On day 1 there were no statistically signi®cant differences in the pharmacokinetics (AUC(0,12 h), C max , t max ) of ziprasidone among subjects with normal renal function and those with mild, moderate and severe renal impairment. The AUC(0,12 h) and C max in subjects with mildly impaired renal function were statistically signi®cantly greater than in those with moderately impaired renal function (P=0.0163±0.0385). The mean AUC(0,12 h) was 272, 370, 250 and 297 ng ml x1 h in groups 1, 2, 3 and 4, respectively. Corresponding mean C max values were 47, 61, 41 and 50 ng ml x 1 and corresponding mean t max values were 5, 6, 5 and 5 h. On day 8 there were no statistically signi®cant differences in the pharmacokinetics (AUC(0,12 h), C max , t max , l z , Fb) of ziprasidone among subjects with normal renal function and those with moderate or severe renal impairment. The AUC(0,12 h) in subjects with mild renal impairment was statistically signi®cantly greater than those in the other three groups (P=0.0025±0.0221), but this was not considered clinically signi®cant. The mean AUC(0,12 h) were 446, 650, 389 and 427 ng ml x 1 h in groups 1, 2, 3 and 4, respectively. Corresponding mean C max values were 68, 93, 54 and 70 ng ml , corresponding mean t max values were 4, 5, 4 and 5 h and corresponding mean l z were 0.14, 0.11, 0.14 and 0.17 h x 1 . The mean percentage Fb was 99.84± 99.88% across all groups and the mean t K,z ranged from 4.2 to 6.4 h. Comparison of the mean AUC(0,12 h) and C max values in subjects with severe renal impairment on day 7 with those on day 8 suggested that haemodialysis does not have a clinically signi®cant effect on the pharmacokinetics of ziprasidone. Conclusions The ®ndings of this study indicate that mild-to-moderate impairment of renal function does not result in clinically signi®cant alteration of ziprasidone pharmacokinetics and therefore does not necessitate dose adjustment.
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