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

Aims To assess whether renal impairment influences the pharmacokinetics of ziprasidone, and to determine whether ziprasidone is cleared via haemodialy sis. 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, creatini ne clearance > 70 ml min(-1)); mildly impaired (group 2, creatinine clearan ce 30-60 ml min(-1)); moderately impaired (group 3, creatinine clearance 10 -29 ml min(-1)), and severely impaired (group 4, requiring haemodialysis th ree times-a-week). Subjects received ziprasidone 40 mg day(-1), given orall y 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 mul tiple 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 significant differences in the pharmacokinetics (AUC(0,12 h), C-max,C- t(max)) of ziprasidone among subje cts with normal renal function and those with mild, moderate and severe ren al impairment. The AUC(0,12 h) and C-max in subjects with mildly impaired r enal function were statistically significantly greater than in those with m oderately impaired renal function (P = 0.0163-0.0385). The mean AUC(0,12 h) was 272, 370, 250 and 297 ng ml(-1) h in groups 1, 2, 3 and 4, respectivel y. Corresponding mean C-max values were 47, 61, 41 and 50 ng ml(-1) and cor responding mean t(max) values were 5, 6, 5 and 5 h. On day 8 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), C-max, t(max), lambda(z), Fb) of ziprasidone among subjects with normal re nal function and those with moderate or severe renal impairment. The AUC(0, 12 h) in subjects with mild renal impairment was statistically significantl y greater than those in the other three groups (P = 0.0025-0.0221), but thi s was not considered clinically significant. The mean AUC(0,12 h) were 446, 650, 389 and 427 ng ml(-1) h in groups 1, 2, 3 and 4, respectively. Corres ponding mean C-max values were 68, 93, 54 and 70 ng ml(-1), corresponding m ean t(max) values were 4, 5, 4 and 5 h and corresponding mean lambda(z) wer e 0.14, 0.11, 0.14 and 0.17 h(-1). The mean percentage Fb was 99.84-99.88% across all groups and the mean t(1/2,z) ranged from 4.2 to 6.4 h. Compariso n of the mean AUC(0,12 h) and C-max values in subjects with severe renal im pairment on day 7 with those on day 8 suggested that haemodialysis does not have a clinically significant effect on the pharmacokinetics of ziprasidon e. Conclusions The findings of this study indicate that mild-to-moderate impai rment of renal function does not result in clinically significant alteratio n of ziprasidone pharmacokinetics and therefore does not necessitate: dose adjustment.