Single‐ and multiple‐dose pharmacokinetics of ziprasidone under non‐fasting conditions in healthy male volunteers

Abstract

Aims To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the in¯uence of ziprasidone on serum prolactin levels. Methods Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at ®xed dosages of 10 and 40 mg day x 1 , and using titrated regimens of 40± 80 and 40±120 mg day , for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double-blind, placebo-controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated.Results Steady-state exposure to ziprasidone was attained after 1 day of dosing. Mean C max and AUC(0,12 h) increased with increasing dose, with apparent doseproportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the ®xed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day x 1 doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side-effect was mild or moderate headache. A minority of patients suffered ®rst-dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance. Conclusions Ziprasidone is characterized by a predictable pharmacokinetic pro®le resulting in symptoms that re¯ect its pharmacological action.

Effects of Olanzapine and Ziprasidone on Glucose Tolerance in Healthy Volunteers

“…This is a limitation of our study, and plasma levels for both ziprasidone and olanzapine were rather low but can still be considered to reach a clinical effective range (Perry et al, 1997;Daniel et al, 1999;Miceli et al, 2000;Mauri et al, 2005). Despite the fact that the doses for olanzapine and ziprasidone are not entirely equivalent in their D(dopamine) 2 blocking ability, it is not likely that D 2 effects account for the results observed.…”

“…As subjects who were administered with ziprasidone took a 40 mg dose in the morning and 40 mg in the evening, this group experienced more side-effects during the day whereas olanzapine doses were administered only in the evening (due to different plasma half-lives; Miceli et al, 2000;Perry et al, 1997) and felt fatigue mostly during night time when they could sleep. This difference in administration could explain the drop out rate for the ziprasidone group (n ¼ 5).…”

Occupancy of Agonist Drugs at the 5-HT1A Receptor

“…The maximum dose is 80 mg twice daily in both regions. Maximum plasma concentration is reached after 4-5 h for a single dose of ziprasidone taken with food, and the half-life is 3.2-4.8 h (Miceli et al, 2000).…”

Atypicality of Atypical Antipsychotics

“…4 Controlled clinical trials suggest that ziprasidone is associated with a low risk of EPS and transient but nondose-related elevations in prolactin. [53][54][55] However, anecdotal experience suggests that the occurrence of EPS during ziprasidone therapy may be more prominent than clinical trials indicate. Unlike clozapine or quetiapine, ziprasidone has a high affinity for D 2 receptors and a very high affinity for 5-HT 2 receptors.…”