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5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic Properties
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
M,-receptors. Antagonism at this receptor has been associated with memory
impairment.
Receptor Functional Studies
Additional preclinical studies were carried ad to identify agonist or
antagonist effects at receptors in which ziprasidone binds with high to
moderate affinity. 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. The
serotonergic and neuronal reuptake properties of ziprasidone are associated
with antidepressant activity. In addition, 5HT1A agonism has been associated
with anxiolytic effects. Potent antagonism at the 5HT2C receptor has been
associated with antipsychotic activity.
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.
5.2 Pharmacokinetic Properties
Following oral administration of multiple doses of ziprasidone with food,
peak serum concentrations typically occur six to eight 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 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
steadystate 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.
In vitro studies indicate that CYP3A4 is the major cytochrome P450
catalyzing the oxidative metabolism of ziprasidone.
S-methyl-dihydroziprasidone is generated in two steps catalyzed by aldehyde
oxidase and thiol methyltransferase.
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 evaluation of ziprasidone serum
concentrations 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 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), 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.
5.3 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 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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of Excipients
Lactose monohydrate, pregelatinized maize starch, magnesium stearate,
gelatin, titanium dioxide, indigotin.
6.2 Incompatibilities (major)
None known.
6.3 Shelf-life
See shelf-life on outer carton.
6.4 Special precautions for storage
Store below 25°C
6.5 Nature and Contents of Container
Ziprasidone capsules are presented in aluminum foil/foil blister strips in
cartons containing 30 or 100 capsules. Not all pack sizes may be marketed.
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