Ziprasidone

Ziprasidone has a high affinity for dopamine type 2 (D₂) receptors and substantially higher affinity for serotonin type 2_A (5HT_2A) receptors. Receptor blockade, 12 hours after a single dose of 40 mg, was greater than 80% for serotonin type 2_A and greater than 50% for D₂ using positron emission tomography (PET). Ziprasidone also interacts with serotonin 5HT_2C, 5HT_1D and 5HT_1A 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 H(1)- and alpha(1)-receptors. Ziprasidone demonstrates negligible affinity for muscarinic M(1)-receptors.

Ziprasidone has been shown to be an antagonist at both serotonin type 2_A (5HT_2A) and dopamine type 2 (D₂) receptors. It is proposed that the therapeutic activity is mediated, in part, through this combination of antagonist activities. Ziprasidone is also a potent antagonist at 5HT_2C and 5HT_1D receptors, a potent agonist at the 5HT_1A receptor and inhibits neuronal reuptake of norepinephrine and serotonin.

Absorption

Following oral administration of multiple doses of ziprasidone with food, peak serum concentrations typically occur 6 to 8 hours post-dose. The absolute bioavailability of a 20 mg dose is 60% in the fed state. Pharmacokinetic studies have demonstrated that the bioavailability of ziprasidone is increased by up to 100% in the presence of food. It is therefore recommended that ziprasidone should be taken with food.

The bioavailability of ziprasidone administered intramuscularly is 100%. After intramuscular administration of single doses, peak serum concentrations typically occur at approximately 30-60 minutes post-dose. Exposure increases in a dose-related manner and following 3 days of intramuscular dosing, little accumulation is observed.

Distribution

The volume of distribution is approximately 1.1 L/kg. Ziprasidone is more than 99% protein bound in serum.

Biotransformation and elimination

Oral administration: The mean terminal half-life of ziprasidone after oral administration is 6.6 hours. Steady state is reached within 1-3 days.

IM administration: The mean terminal half-life on the third day of dosing ranged from 8 to 10 hours. The mean terminal half-life of ziprasidone after intravenous administration is 6 hours.

Mean clearance of ziprasidone administered intravenously is 5 ml/min/kg. Approximately 20% of the dose is excreted in urine, and approximately 66% is eliminated in faeces.

Ziprasidone demonstrates linear kinetics over the therapeutic dose range of 40 to 80 mg twice daily in fed subjects.

Ziprasidone is extensively metabolised after oral administration with only a small amount excreted in urine (<1%) or faeces (<4%) as unchanged ziprasidone. Ziprasidone is primarily cleared via three proposed metabolic routes to yield four major circulating metabolites, benzisothiazole piperazine (BITP) sulphoxide, BITP sulphone, ziprasidone sulphoxide and S-methyldihydroziprasidone. Unchanged ziprasidone represents about 44% of total drug-related material in serum.

Ziprasidone is primarily metabolised by two pathways: reduction and methylation to generate S-methyldihydroziprasidone 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‑methyldihydroziprasidone 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 catalysing the oxidative metabolism of ziprasidone with a potential minor contribution of CYP1A2.

Ziprasidone, S-methyldihydroziprasidone, and ziprasidone sulphoxide, when tested in vitro, share properties which may predict a QTc-prolonging effect. S-methyldihydroziprasidone is mainly eliminated in faeces by biliary excretion with a minor contribution by CYP3A4 catalysed metabolism. Ziprasidone sulphoxide is eliminated through renal excretion and by secondary metabolism catalysed by CYP3A4.

Special populations

Pharmacokinetic screening of patients has not revealed any significant pharmacokinetic differences between smokers and non-smokers.

No clinically significant age- or gender-differences in the pharmacokinetics were observed following oral administration. The pharmacokinetics of ziprasidone in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights.

Consistent with the fact that renal clearance contributes very little to its overall clearance, no progressive increases in ziprasidone exposure were noted when ziprasidone was administered to subjects with varying degrees of renal function. Exposures in subjects with mild (creatinine clearance 30-60 ml/min), moderate (creatinine clearance 10-29 ml/min) and severe impairment (requiring dialysis) were 146%, 87% and 75% those of healthy subjects (creatinine clearance >70 ml/min) following oral administration of 20 mg BID for seven days. It is unknown whether serum concentrations of the metabolites are increased in these patients.

In mild to moderate impairment of liver function (Child Pugh A or B) caused by cirrhoses, the serum concentrations after oral administration were 30% higher and the terminal half-life was about 2 hours longer than in normal patients. The effect of liver impairment on the serum concentrations of the metabolites is unknown.

Preclinical safety data reveal 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. Undesirable effects on fertility and decreased pup weights were observed at doses causing maternal toxicity such as 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.