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The pharmacokinetics of ziprasidone in subjects with normal and impaired renal function
Author(s) -
Aweeka F.,
Jayesekara D.,
Horton M.,
Swan S.,
Lambrecht L.,
Wilner K. D.,
Sherwood J.,
Anziano R. J.,
Smolarek T. A.,
Turncliff R. Z.
Publication year - 2000
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2000.00150.x
Subject(s) - ziprasidone , pharmacokinetics , impaired renal function , renal function , medicine , metabolic clearance rate , pharmacology , schizophrenia (object oriented programming) , psychiatry , antipsychotic
Aims To assess whether renal impairment influences 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 − 1 ); mildly impaired (group 2, creatinine clearance 30–60 ml min − 1 ); moderately impaired (group 3, creatinine clearance 10–29 ml min − 1 ), and severely impaired (group 4, requiring haemodialysis three times‐a‐week). Subjects received ziprasidone 40 mg day − 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 significant 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 significantly 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 −1 h in groups 1, 2, 3 and 4, respectively. Corresponding mean C max values were 47, 61, 41 and 50 ng ml − 1 and corresponding 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 , λ 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 significantly greater than those in the other three groups ( P =0.0025–0.0221), but this 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. Corresponding mean C max values were 68, 93, 54 and 70 ng ml − 1 , corresponding mean t max values were 4, 5, 4 and 5 h and corresponding mean λ z were 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 ½,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 significant effect on the pharmacokinetics of ziprasidone. Conclusions The findings of this study indicate that mild‐to‐moderate impairment of renal function does not result in clinically significant alteration of ziprasidone pharmacokinetics and therefore does not necessitate dose adjustment.