Pharmacology: Pharmacodynamics: Receptor Binding Studies: Ziprasidone has a high affinity for dopamine type 2 (D2) receptors and substantially higher affinity for serotonin type 2A (5HT2A) receptors. Ziprasidone also interacts with serotonin 5HT2C, 5HT1D and 5HT1A receptors where its affinities for these sites are equal to or greater than its affinity for the D2 receptor. Ziprasidone has moderate affinity for neuronal serotonin and norepinephrine transporters. Ziprasidone demonstrates moderate affinity for histamine H1- and alpha1-receptors. Antagonism at these receptors has been associated with somnolence and orthostatic hypotension, respectively. Ziprasidone demonstrates negligible affinity for muscarinic M1-receptors. Antagonism at this receptor has been associated with memory impairment.
Receptor Functional Studies: Ziprasidone has been shown to be an antagonist at both serotonin type 2A (5HT2A) and dopamine type 2 (D2) receptors. It is proposed that the antipsychotic activity is mediated, in part, through this combination of antagonist activities.
Ziprasidone is also a potent antagonist at 5HT2C and 5HT1D receptors, a potent agonist at the 5HT1A receptor and inhibits neuronal reuptake of norepinephrine and serotonin.
Human PET Studies: At 12 hours following a 40 mg oral dose of ziprasidone, receptor blockade was greater than 80% for 5HT2A and greater than 50% for D2 using positron emission tomography (PET).
Further Information from Clinical Trials: In a double-blind comparative study, metabolic parameters including weight, fasting levels of total cholesterol, triglycerides, insulin and an insulin resistance (IR) index were measured. In patients receiving ziprasidone no significant changes from baseline were observed in any of these metabolic parameters.
Results of a Large Post-Marketing Safety Study: A randomized post-approval study of 18,239 patients with observational follow-up for 1 year was conducted to determine whether ziprasidone's effect on the QTc interval is associated with an increased risk of non-suicide mortality in patients with schizophrenia. This study, which was conducted in naturalistic clinical practice settings, showed no difference in the rate of non-suicide mortality between ziprasidone and olanzapine treatments.
Pharmacokinetics: Following oral administration of multiple doses of ziprasidone with food, peak serum concentrations typically occur 6 to 8 hours post-dose. Ziprasidone demonstrates linear kinetics over the therapeutic dose range of 40-80 mg twice daily in fed subjects.
The absolute bioavailability of a 20 mg dose is 60% in the fed state. The absorption of ziprasidone is reduced by up to 50% when ziprasidone is administered under fasting conditions. In a multiple dose study, ziprasidone oral suspension was shown to be bioequivalent to ziprasidone capsules under steady-state conditions. In a single dose administration study, bioequivalence was demonstrated with regard to AUC. A slightly lower Cmax was achieved with oral suspension than with capsules.
Twice daily dosing generally leads to attainment of steady state within three days. Systemic exposures at steady state are related to dose.
At steady-state, the mean terminal elimination half-life of ziprasidone is about 6.6 hours following oral dosing. Mean systemic clearance of ziprasidone administered intravenously is 7.5 mL/min/kg and the volume of distribution is approximately 1.5 L/kg. Ziprasidone is extensively bound (>99%) to plasma proteins and its binding appears to be independent of concentration.
Ziprasidone is extensively metabolized after oral administration with only a small amount (<1%) excreted in urine or feces (<4%) as unchanged drug. Ziprasidone is primarily cleared via three metabolic routes to yield four major circulating metabolites, benzisothiazole piperazine (BITP) sulphoxide, BITP sulphone, ziprasidone sulphoxide and S-methyl-dihydroziprasidone. Approximately 20% of the dose is excreted in urine, with approximately 66% being eliminated in feces. Unchanged ziprasidone represents about 44% of total drug-related material in serum.
Ziprasidone is primarily metabolized by two pathways: reduction and methylation to generate S-methyl-dihydroziprasidone which accounts for approximately two-thirds of the metabolism, and oxidative metabolism accounting for the other third. In vitro studies using human liver subcellular fractions indicate that S-methyl-dihydroziprasidone is generated in two steps. These studies indicate that the first step is mediated primarily by chemical reduction by glutathione as well as by enzymatic reduction by aldehyde oxidase. The second step is methylation mediated by thiol methyltransferase. In vitro studies indicate that CYP3A4 is the major cytochrome P450 catalyzing the oxidative metabolism of ziprasidone.
Ziprasidone, S-methyl-dihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro, share properties which may predict a QTc-prolonging effect. S-methyl-dihydroziprasidone is mainly eliminated by fecal excretion and CYP3A4 catalyzed metabolism. The sulphoxide is eliminated through renal extraction and by secondary metabolism catalyzed by CYP3A4.
In a phase I trial, the CYP3A4 inhibitor ketoconazole (400 mg/day) increased the serum concentrations of ziprasidone by <40%. The serum concentration of S-methyl-dihydroziprasidone, at the expected Tmax of ziprasidone, was increased by 55% during ketoconazole treatment. No additional QTc prolongation was observed.
No clinically significant differences in the pharmacokinetics of ziprasidone in young and elderly male or female subjects were observed following oral administration.
Pharmacokinetic screening of patients treated orally has not revealed any significant pharmacokinetic differences between smokers and non-smokers.
No marked differences in the pharmacokinetics of oral ziprasidone have been observed in patients with moderate to severe impairments in renal function as compared to subjects with normal renal function. It is unclear whether serum concentrations of the metabolites are increased in these patients.
In mild to moderate impairment of liver function (Child-Pugh A or B), the serum concentrations of ziprasidone after oral administration were 30% higher and the terminal half-life was about two hours longer than in normal subjects.
Toxicology: Preclinical Safety Data: Preclinical safety data on ziprasidone revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential. In reproductive studies in rats and rabbits, ziprasidone has shown no evidence of teratogenicity. Adverse effects on fertility and increased numbers of pups born dead, decreased pup weights and delayed functional development were observed at doses that caused adverse effects suggestive of maternal toxicity (e.g., sedation, decreased body weight gain). Increased perinatal mortality and delayed functional development of offspring occurred at maternal plasma concentrations extrapolated to be similar to the maximal concentrations in humans given therapeutic doses.