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

Abstract

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.

Special considerations in the treatment of patients with bipolar disorder and medical co-morbidities

“…Dosage adjustment is recommended in renal disease [60]. The pharmacokinetics of olanzapine, quetiapine, and oral ziprasidone are not altered in renal disease [76,77]. Though the intramuscular formulation of ziprasidone has not been studied in patients with renal impairment, because the cyclodextrin excipient is renally cleared it is suggested that it be administered with caution to patients with renal impairment [78].…”

Prediction of Ligands Binding Acetylcholinesterase with Potential Antidotal Activity: A Virtual Screening Approach

“…In fact, the molecular weight of triamterene is 253 g/mol, meaning that 1 nM is equal to 0.253 ng/mL, if our calculated Ki is 31.3 nM, it is equivalent to 7.9 ng/mL, below the maximal concentration of 125 ng/mL that was achieved in humans after an oral single dose of 100 mg . Regarding ziprasidone, using a similar approach, the plasma concentrations obtained after a therapeutic oral dose of 20 mg was 47 ng/mL, that is higher than 4 ng/mL (9.7 nM) corresponding to our calculated Ki for this drug.…”

Psychotic symptoms in patients with medical disorders

“…Similarly, the pharmacokinetics of risperidone were not significantly altered in cirrhosis patients [70]. Unfortunately, there is no liver function test, or combination of tests, that can quantify impairment of liver function in a manner analogous to serum creatinine or creatinine clearance for renal impairment [71]. Because antipsychotics are considerably protein bound, the reduced protein production in chronic liver disease results in an increased free fraction of the medication.…”

“…For the other atypical antipsychotics, dose adjustments in renal failure have not specifically been recommended. For example, the pharmacokinetics of ziprasidone are not significantly affected by mild-moderate renal impairment or by hemodialysis [71].…”