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).
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.
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.
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.
Special Populations
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.
Ziprasidone intramuscular has not been systematically evaluated in elderly patients
(65 years and over).
Race – No specific pharmacokinetic study was conducted to investigate
the effects of race. Population pharmacokinetic evaluation has revealed no evidence
of clinically significant race-related differences in the pharmacokinetics of ziprasidone.
Dosage modifications for race 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.
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.
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 BID 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.
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.
Drug-Drug Interactions
An in vitro enzyme inhibition study utilizing human liver microsomes showed
that ziprasidone had little inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6
and CYP3A4, and thus would not likely interfere with the metabolism of drugs primarily
metabolized by these enzymes. In vivo studies have revealed no effect of
ziprasidone on the pharmacokinetics of dextromethorphan, estrogen, progesterone,
or lithium (see Drug Interactions under PRECAUTIONS).
In vivo studies have revealed an approximately 35% decrease in ziprasidone
AUC by concomitantly administered carbamazepine, an approximately 35-40% increase
in ziprasidone AUC by concomitantly administered ketoconazole, but no effect on
ziprasidone’s pharmacokinetics by cimetidine or antacid (see Drug Interactions
under PRECAUTIONS).