the effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel Atypical Antipsychotic Agent ziprasidone

Study Objective. To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel Atypical Antipsychotic drug ziprasidone.

Design. Open, randomized, three-way crossover study.

Setting. University-based research facility.

Subjects. Eight healthy male volunteers.

Interventions. Ziprasidone 20 mg was administered under fasting conditions (treatment A), and directly after (treatment B) and 2 hours after (treatment C) a standard high-fat breakfast.

Measurements and Main Results. Serial blood samples were obtained over 36 hours. Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose. Ziprasidone had a significant effect on area under the curve (AUC0-∞), maximum serum concentration, and half-life (analysis of variance all p 0.016).

Conclusion. These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods, possibly due to improved drug dissolution and solubilization. The drug’s longer half-life under fasting conditions may reflect dissolution-limited absorption, although this could not be directly assessed. Despite postprandial increases in ziprasidone AUC0-∞ and maximum concentration, daytime vigilance was not affected.

the effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel Atypical Antipsychotic Agent ziprasidone

Study Objective. To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel Atypical Antipsychotic drug ziprasidone.

Design. Open, randomized, three-way crossover study.

Setting. University-based research facility.

Subjects. Eight healthy male volunteers.

Interventions. Ziprasidone 20 mg was administered under fasting conditions (treatment A), and directly after (treatment B) and 2 hours after (treatment C) a standard high-fat breakfast.

Measurements and Main Results. Serial blood samples were obtained over 36 hours. Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose. Ziprasidone had a significant effect on area under the curve (AUC0-∞), maximum serum concentration, and half-life (analysis of variance all p 0.016).

Conclusion. These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods, possibly due to improved drug dissolution and solubilization. The drug’s longer half-life under fasting conditions may reflect dissolution-limited absorption, although this could not be directly assessed. Despite postprandial increases in ziprasidone AUC0-∞ and maximum concentration, daytime vigilance was not affected.

Quetiapine extended release: in schizophrenia.

▴ Quetiapine is an Atypical Antipsychotic Agent with well established efficacy and tolerability in the acute and maintenance treatment of adults with schizophrenia.

Aripiprazole

▴ Aripiprazole, an oral quinolinone, is the first Atypical Antipsychotic Agent to be approved in the US as adjunctive treatment in adult patients with major depressive disorder (MDD). ▴ In two large, well-designed trials in patients with MDD who had an inadequate response to standard antidepressant therapy, 6 weeks’ adjunctive therapy with aripiprazole 2–20 mg/day improved mean Montgomery Asberg Depression Rating Scale (MADRS) total scores (primary endpoint) to a significantly greater extent than adjunctive placebo treatment. ▴ Improvements in mean MADRS total score during the double-blind phase favoured adjunctive aripiprazole treatment from 1–2 weeks onward, with per-protocol subgroup analyses showing that mean changes were not affected by the specific standard antidepressant therapy used, age or sex of the pa-tient or the mean MADRS total scores at the start of double-blind adjunctive therapy. ▴. In general, secondary endpoint scores, including those for the Sheehan Disability Scale, Clinical Global Impression (CGI) Improvement scale and CGI Severity of Illness scale, improved to a significantly greater extent with adjunctive aripiprazole than with adjunctive placebo treatment, with significantly higher response and remission rates in the aripiprazole groups. ▴ In these two pivotal trials, adjunctive aripiprazole 2–20 mg/day was generally well tolerated, with most treatment-emergent adverse events being of mild to moderate severity.

Ziprasidone

Ziprasidone (Geodon®, Zeldox®) is an Atypical Antipsychotic Agent with a unique neurotransmitter receptor-binding profile. The oral formulation is indicated for the treatment of adult patients with schizophrenia and the intramuscular formulation for the control of acute agitation in these patients. In adult patients with schizophrenia or schizoaffective disorder, oral ziprasidone was effective at a dosage of 40–80mg twice daily in patients experiencing a phase of acute illness, and at a dosage of 20–80mg twice daily in those with chronic schizophrenia or schizoaffective disorder, including those who were symptomatically stable. Ziprasidone offers the advantage over most other Atypical Antipsychotic Agents of being available in a fast-acting intramuscular formulation for control of acute agitation, thus providing clinicians with the option to safely and effectively transition to longer-term treatment with the oral formulation. Although careful consideration should be given to the propensity for ziprasidone to cause corrected QT (QTc) interval prolongation, albeit at a relatively low incidence, the drug generally has a favourable tolerability profile of low extrapyramidal syndrome (EPS) liability, neutral bodyweight gain, and potentially low propensity for metabolic complications. Thus, ziprasidone is an effective option for the management of patients with schizophrenia or schizoaffective disorder, with the intramuscular formulation providing a useful option for the treatment of acute agitation in these patients. Pharmacological Properties Ziprasidone is a potent serotonin 5-HT_2A and dopamine D_2 receptor antagonist. It has a higher binding affinity for the 5-HT_2A receptor than the D_2 receptor, which may, in part, explain the beneficial effects the drug has against the negative symptoms of schizophrenia and the low risk for EPS. The pharmacological profile of ziprasidone suggests a low potential for bodyweight gain, which was confirmed in clinical trials in patients with schizophrenia or schizoaffective disorder. In addition, ziprasidone was not associated with dyslipidaemia. The oral formulation of ziprasidone 20–60mg twice daily is well absorbed, with a maximum plasma drug concentration of 45–139 ng/mL. Systemic exposure was greater in the fed state than in the fasted state; thus oral ziprasidone should be taken with food. Ziprasidone is extensively metabolised in the liver, with