Mechanism of Action
The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia,
is unknown. However, it has been proposed that this drug's efficacy in schizophrenia
is mediated through a combination of dopamine type 2 (D2)
and serotonin type 2 (5HT2) antagonism. As with other
drugs having efficacy in bipolar disorder, the mechanism of action of ziprasidone
in bipolar disorder is unknown.
Pharmacodynamics
Ziprasidone exhibited high in vitro binding affinity for the dopamine D2
and D3, the serotonin 5HT2A,
5HT2C, 5HT1A, 5HT1D,
and α1-adrenergic receptors (Ki
s of 4.8, 7.2, 0.4, 1.3, 3.4, 2, and 10 nM, respectively), and moderate affinity
for the histamine H1 receptor (Ki=47
nM). Ziprasidone functioned as an antagonist at the D2,
5HT2A, and 5HT1D receptors,
and as an agonist at the 5HT1A receptor. Ziprasidone inhibited
synaptic reuptake of serotonin and norepinephrine. No appreciable affinity was exhibited
for other receptor/binding sites tested, including the cholinergic muscarinic receptor
(IC50 >1 µM). Antagonism at receptors other than dopamine
and 5HT2 with similar receptor affinities may explain some of the
other therapeutic and side effects of ziprasidone. Ziprasidone's antagonism of histamine H1
receptors may explain the somnolence observed with this drug. Ziprasidone's antagonism
of α1-adrenergic receptors may explain the orthostatic
hypotension observed with this drug.
Pharmacokinetics
Oral Pharmacokinetics
Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics
of ziprasidone are dose-proportional within the proposed clinical dose range, and
ziprasidone accumulation is predictable with multiple dosing. Elimination of ziprasidone
is mainly via hepatic metabolism with a mean terminal half-life of about 7 hours
within the proposed clinical dose range. Steady-state concentrations are achieved
within one to three days of dosing. The mean apparent systemic clearance is 7.5
mL/min/kg. Ziprasidone is unlikely to interfere with the metabolism of drugs metabolized
by cytochrome P450 enzymes.
Absorption: Ziprasidone is well absorbed after oral administration, reaching
peak plasma concentrations in 6 to 8 hours. The absolute bioavailability of a 20
mg dose under fed conditions is approximately 60%. The absorption of ziprasidone
is increased up to two-fold in the presence of food.
Distribution: Ziprasidone has a mean apparent volume of distribution of 1.5
L/kg. It is greater than 99% bound to plasma proteins, binding primarily to albumin
and α1-acid glycoprotein. The in vitro plasma protein
binding of ziprasidone was not altered by warfarin or propranolol, two highly protein-bound
drugs, nor did ziprasidone alter the binding of these drugs in human plasma. Thus,
the potential for drug interactions with ziprasidone due to displacement is minimal.
Metabolism and Elimination: Ziprasidone is extensively metabolized after
oral administration with only a small amount excreted in the urine (<1%) or feces
(<4%) as unchanged drug. Ziprasidone is primarily cleared via three metabolic
routes to yield four major circulating metabolites, benzisothiazole (BITP) sulphoxide,
BITP-sulphone, ziprasidone sulphoxide, and S-methyl-dihydroziprasidone. Approximately
20% of the dose is excreted in the urine, with approximately 66% being eliminated
in the feces. Unchanged ziprasidone represents about 44% of total drug-related material
in serum. In vitro studies using human liver subcellular fractions indicate
that S-methyl-dihydroziprasidone is generated in two steps. The data indicate that
the reduction reaction is mediated by aldehyde oxidase and the subsequent methylation
is mediated by thiol methyltransferase. In vitro studies using human liver
microsomes and recombinant enzymes indicate that CYP3A4 is the major CYP contributing
to the oxidative metabolism of ziprasidone. CYP1A2 may contribute to a much lesser
extent. Based on in vivo abundance of excretory metabolites, less than one-third
of ziprasidone metabolic clearance is mediated by cytochrome P450 catalyzed oxidation
and approximately two-thirds via reduction by aldehyde oxidase. There are no known
clinically relevant inhibitors or inducers of aldehyde oxidase.
Intramuscular Pharmacokinetics
Systemic Bioavailability: The bioavailability of ziprasidone administered
intramuscularly is 100%. After intramuscular administration of single doses, peak
serum concentrations typically occur at approximately 60 minutes post-dose or earlier
and the mean half-life (T1/2) ranges from two to five
hours. Exposure increases in a dose-related manner and following three days of intramuscular
dosing, little accumulation is observed.
Metabolism and Elimination: Although the metabolism and elimination of IM
ziprasidone have not been systematically evaluated, the intramuscular route of administration
would not be expected to alter the metabolic pathways.
USE IN SPECIFIC POPULATIONS
Pregnancy – Pregnancy Category C - In animal studies ziprasidone demonstrated developmental toxicity,
including possible teratogenic effects at doses similar to human therapeutic doses. When
ziprasidone was administered to pregnant rabbits during the period of organogenesis, an increased
incidence of fetal structural abnormalities (ventricular septal defects and other cardiovascular
malformations and kidney alterations) was observed at a dose of 30 mg/kg/day (3 times the MRHD
of 200 mg/day on a mg/m2 basis). There was no evidence to suggest that these developmental
effects were secondary to maternal toxicity. The developmental no-effect dose was 10 mg/kg/day
(equivalent to the MRHD on a mg/m2 basis). In rats, embryofetal toxicity (decreased fetal
weights, delayed skeletal ossification) was observed following administration of 10 to 160 mg/kg/day
(0.5 to 8 times the MRHD on a mg/m2 basis) during organogenesis or throughout gestation,
but there was no evidence of teratogenicity. Doses of 40 and 160 mg/kg/day (2 and 8 times the MRHD
on a mg/m2 basis) were associated with maternal toxicity. The developmental no-effect dose
was 5 mg/kg/day (0.2 times the MRHD on a mg/m2 basis).
There was an increase in the number of pups born dead and a decrease in postnatal survival through the
first 4 days of lactation among the offspring of female rats treated during gestation and lactation with
doses of 10 mg/kg/day (0.5 times the MRHD on a mg/m2 basis) or greater. Offspring developmental
delays and neurobehavioral functional impairment were observed at doses of 5 mg/kg/day (0.2 times the MRHD
on a mg/m2 basis) or greater. A no-effect level was not established for these effects.
There are no adequate and well-controlled studies in pregnant women. Ziprasidone should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Labor and Delivery – The effect of ziprasidone on labor and delivery in humans is unknown.
Nursing Mothers – It is not known whether ziprasidone or its metabolites are excreted in human milk. It is recommended that
women receiving ziprasidone should not breastfeed.
Pediatric Use – The safety and effectiveness of ziprasidone in pediatric patients have not been established.
Geriatric Use – Of the total number of subjects in clinical studies of ziprasidone, 2.4 percent were 65 and over. No
overall differences in safety or effectiveness were observed between these subjects and younger subjects,
and other reported clinical experience has not identified differences in responses between the elderly and
younger patients, but greater sensitivity of some older individuals cannot be ruled out. Nevertheless, the
presence of multiple factors that might increase the pharmacodynamic response to ziprasidone, or cause poorer
tolerance or orthostasis, should lead to consideration of a lower starting dose, slower titration, and careful
monitoring during the initial dosing period for some elderly patients.
Ziprasidone intramuscular has not been systematically evaluated in elderly patients (65 years and over).
Renal Impairment – Because ziprasidone is highly metabolized, with
less than 1% of the drug excreted unchanged, renal impairment alone is unlikely
to have a major impact on the pharmacokinetics of ziprasidone. The pharmacokinetics
of ziprasidone following 8 days of 20 mg BID dosing were similar among subjects
with varying degrees of renal impairment (n=27), and subjects with normal renal
function, indicating that dosage adjustment based upon the degree of renal impairment
is not required. Ziprasidone is not removed by hemodialysis.
Intramuscular ziprasidone has not been systematically evaluated in elderly patients
or in patients with hepatic or renal impairment. As the cyclodextrin excipient is
cleared by renal filtration, ziprasidone intramuscular should be administered with
caution to patients with impaired renal function [see Clinical Pharmacology].
Hepatic Impairment – As ziprasidone is cleared substantially by
the liver, the presence of hepatic impairment would be expected to increase the
AUC of ziprasidone; a multiple-dose study at 20 mg twice daily for 5 days in subjects (n=13)
with clinically significant (Childs-Pugh Class A and B) cirrhosis revealed an increase
in AUC 0-12 of 13% and 34% in Childs-Pugh Class A and
B, respectively, compared to a matched control group (n=14). A half-life of 7.1
hours was observed in subjects with cirrhosis compared to 4.8 hours in the control
group.
Age and Gender Effects – In a multiple-dose (8 days of treatment)
study involving 32 subjects, there was no difference in the pharmacokinetics of
ziprasidone between men and women or between elderly (>65 years) and young (18
to 45 years) subjects. Additionally, population pharmacokinetic evaluation of patients
in controlled trials has revealed no evidence of clinically significant age or gender-related
differences in the pharmacokinetics of ziprasidone. Dosage modifications for age
or gender are, therefore, not recommended.
Smoking – Based on in vitro studies utilizing human liver
enzymes, ziprasidone is not a substrate for CYP1A2; smoking should therefore not
have an effect on the pharmacokinetics of ziprasidone. Consistent with these in vitro
results, population pharmacokinetic evaluation has not revealed any significant
pharmacokinetic differences between smokers and nonsmokers.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Lifetime carcinogenicity studies were conducted with ziprasidone in Long Evans rats and CD-1 mice.
Ziprasidone was administered for 24 months in the diet at doses of 2, 6, or 12 mg/kg/day to rats,
and 50, 100, or 200 mg/kg/day to mice (0.1 to 0.6 and 1 to 5 times the maximum recommended human dose
[MRHD] of 200 mg/day on a mg/m2 basis, respectively). In the rat study, there was no evidence of an
increased incidence of tumors compared to controls. In male mice, there was no increase in incidence of
tumors relative to controls. In female mice, there were dose-related increases in the incidences of pituitary
gland adenoma and carcinoma, and mammary gland adenocarcinoma at all doses tested (50 to 200 mg/kg/day or
1 to 5 times the MRHD on a mg/m2 basis). Proliferative changes in the pituitary and mammary glands of rodents
have been observed following chronic administration of other antipsychotic agents and are considered to be
prolactin-mediated. Increases in serum prolactin were observed in a 1-month dietary study in female, but not
male, mice at 100 and 200 mg/kg/day (or 2.5 and 5 times the MRHD on a mg/m2 basis). Ziprasidone had no effect
on serum prolactin in rats in a 5-week dietary study at the doses that were used in the carcinogenicity study.
The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown
[see Warnings and Precautions].
Mutagenesis
Ziprasidone was tested in the Ames bacterial mutation assay, the in vitro mammalian cell gene mutation mouse
lymphoma assay, the in vitro chromosomal aberration assay in human lymphocytes, and the in vivo chromosomal
aberration assay in mouse bone marrow. There was a reproducible mutagenic response in the Ames assay in one strain
of S. typhimurium in the absence of metabolic activation. Positive results were obtained in both the
in vitro mammalian cell gene mutation assay and the in vitro chromosomal aberration assay in human lymphocytes.
Impairment of Fertility
Ziprasidone was shown to increase time to copulation in Sprague-Dawley rats in two fertility and early embryonic
development studies at doses of 10 to 160 mg/kg/day (0.5 to 8 times the MRHD of 200 mg/day on a mg/m2
basis). Fertility rate was reduced at 160 mg/kg/day (8 times the MRHD on a mg/m2 basis). There was
no effect on fertility at 40 mg/kg/day (2 times the MRHD on a mg/m2 basis). The effect on fertility
appeared to be in the female since fertility was not impaired when males given 160 mg/kg/day (8 times the MRHD on a mg/m2
basis) were mated with untreated females. In a 6-month study in male rats given 200 mg/kg/day (10 times the MRHD on a mg/m2
basis) there were no treatment-related findings observed in the testes.