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

Aims To evaluate the pharmacokinetics and tolerability of single and multip le oral doses of ziprasidone in healthy male volunteers, and to determine t he influence of ziprasidone on serum prolactin levels. Methods Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day(-1), and using t itrated regimens of 40-80 and 40-120 mg day(-1), for 14 days. All dosages w ere taken immediately after food. The study adopted a randomized, double-bl ind, placebo-controlled design. Prolactin response, sedative properties, to lerability, and extrapyramidal symptoms were also investigated. Results Steady-state exposure to ziprasidone was attained after 1 day of do sing. Mean C-max and AUC(0,12h) increased with increasing dose, with appare nt dose-proportionality between the 20 and 60 mg dose levels. Trough-to-pea k ratios at steady state ranged from 2 to 5. Accumulation ratios fbr the fi xed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respec tively. Ziprasidone was associated with transient prolactin elevation but l evels of prolactin returned to baseline within the dosing interval at stead y state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day(-1) doses, and which w as noted to attenuate with chronic dosing. Ziprasidone was generally well t olerated. The most frequent side-effect was mild or moderate headache. A mi nority of patients suffered first-dose postural hypotension. Ziprasidone wa s also associated with a mild sedative effect that became less pronounced a s treatment continued. There were no drug-related changes in electrocardiog ram or clinical laboratory variables that were of clinical importance. Conclusions Ziprasidone is characterized by a predictable pharmacokinetic p rofile resulting in symptoms that reflect its pharmacological action.