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 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 titrated regimens of 40-80 and 40-120 mg day(-1), 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 Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed-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(-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 first-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 profile resulting in symptoms that reflect its pharmacological action.

Figure 1

Serum concentration–time profiles following administration of single (a) and multiple (b) oral doses of ziprasidone to healthy male volunteers immediately after food. Dosages of ziprasidone were 10 mg day⁻¹ (•), 40 mg day⁻¹ (□), 40–80 mg day⁻¹ (▴) and 40–120 mg day⁻¹ (◊).

Figure 2

Mean change from baseline in sum of sedation scores on day 18 profiles following administration of multiple oral doses of ziprasidone 10 mg day⁻¹ (•), 40 mg day⁻¹ (□), 40–80 mg day⁻¹ (▴) and 40–120 mg day⁻¹ (◊), or placebo (+), to healthy male volunteers immediately after food.