A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Abilify Pharmacology, Pharmacokinetics, Studies, Metabolism - Aripiprazole
Abilify Pharmacology, Pharmacokinetics, Studies, Metabolism - Aripiprazole
CLINICAL PHARMACOLOGY
Pharmacodynamics
Aripiprazole exhibits high affinity for dopamine D2 and D3,
serotonin 5-HT1A and 5-HT2A receptors (Ki values
of 0.34, 0.8, 1.7, and 3.4 nM, respectively), moderate affinity for dopamine
D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic
and histamine H1 receptors (Ki values of 44, 15, 39, 57, and 61 nM,
respectively), and moderate affinity for the serotonin reuptake site (Ki=98
nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors
(IC50>1000 nM). Aripiprazole functions as a partial agonist at the
dopamine D2 and the serotonin 5-HT1A receptors, and as
an antagonist at serotonin 5-HT2A receptor.
The mechanism of action of aripiprazole, as with other drugs
having efficacy in schizophrenia, is unknown. However, it has been proposed
that the efficacy of aripiprazole is mediated through a combination of partial
agonist activity at D2 and 5-HT1A receptors and antagonist
activity at 5-HT2A receptors. Actions at receptors other than D2,
5-HT1A, and 5-HT2A may explain some of the other clinical
effects of aripiprazole, eg, the orthostatic hypotension observed with aripiprazole
may be explained by its antagonist activity at adrenergic alpha1
receptors.
Pharmacokinetics
ABILIFY activity is presumably primarily due to the parent
drug, aripiprazole, and to a lesser extent, to its major metabolite, dehydro-aripiprazole,
which has been shown to have affinities for D2 receptors similar
to the parent drug and represents 40% of the parent drug exposure in plasma.
The mean elimination half-lives are about 75 hours and 94 hours for aripiprazole
and dehydro-aripiprazole, respectively. Steady-state concentrations are attained
within 14 days of dosing for both active moieties. Aripiprazole accumulation
is predictable from single-dose pharmacokinetics. At steady state, the pharmacokinetics
of aripiprazole are dose-proportional. Elimination of aripiprazole is mainly
through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.
Absorption
Aripiprazole is well absorbed, with peak plasma concentrations
occurring within 3 to 5 hours; the absolute oral bioavailability of the tablet
formulation is 87%. ABILIFY can be administered with or without food. Administration
of a 15-mg ABILIFY tablet with a standard high-fat meal did not significantly
affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole,
but delayed Tmax by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole.
Distribution
The steady-state volume of distribution of aripiprazole following
intravenous administration is high (404 L or 4.9 L/kg), indicating extensive
extravascular distribution. At therapeutic concentrations, aripiprazole and
its major metabolite are greater than 99% bound to serum proteins, primarily
to albumin. In healthy human volunteers administered 0.5 to 30 mg/day aripiprazole
for 14 days, there was dose-dependent D2-receptor occupancy indicating
brain penetration of aripiprazole in humans.
Metabolism and Elimination
Aripiprazole is metabolized primarily by three biotransformation
pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in
vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation
and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4.
Aripiprazole is the predominant drug moiety in the systemic circulation. At
steady state, dehydro-aripiprazole, the active metabolite, represents about
40% of aripiprazole AUC in plasma.
Approximately 8% of Caucasians lack the capacity to metabolize
CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the
rest are extensive metabolizers (EM). PMs have about an 80% increase in aripiprazole
exposure and about a 30% decrease in exposure to the active metabolite compared
to EMs, resulting in about a 60% higher exposure to the total active moieties
from a given dose of aripiprazole compared to EMs. Coadministration of ABILIFY
with known inhibitors of CYP2D6, like quinidine in EMs, results in a 112% increase
in aripiprazole plasma exposure, and dosing adjustment is needed (see PRECAUTIONS:
Drug-Drug Interactions). The mean elimination
half-lives are about 75 hours and 146 hours for aripiprazole in EMs and PMs,
respectively. Aripiprazole does not inhibit or induce the CYP2D6 pathway.
Following a single oral dose of [14C]-labeled aripiprazole,
approximately 25% and 55% of the administered radioactivity was recovered in
the urine and feces, respectively. Less than 1% of unchanged aripiprazole was
excreted in the urine and approximately 18% of the oral dose was recovered unchanged
in the feces.
Special Populations
In general, no dosage adjustment for ABILIFY is required on
the basis of a patient’s age, gender, race, smoking status, hepatic function,
or renal function (see DOSAGE AND ADMINISTRATION:
Dosage in Special Populations). The pharmacokinetics of aripiprazole in
special populations are described below.
Hepatic Impairment
In a single-dose study (15 mg of aripiprazole) in subjects
with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C), the
AUC of aripiprazole, compared to healthy subjects, increased 31% in mild HI,
increased 8% in moderate HI, and decreased 20% in severe HI. None of these differences
would require dose adjustment.
Renal Impairment
In patients with severe renal impairment (creatinine clearance
<30 mL/min), Cmax of aripiprazole (given in a single dose of 15 mg) and dehydro-aripiprazole
increased by 36% and 53%, respectively, but AUC was 15% lower for aripiprazole
and 7% higher for dehydro-aripiprazole. Renal excretion of both unchanged aripiprazole
and dehydro-aripiprazole is less than 1% of the dose. No dosage adjustment is
required in subjects with renal impairment.
Elderly
In formal single-dose pharmacokinetic studies (with aripiprazole
given in a single dose of 15 mg), aripiprazole clearance was 20% lower in elderly
(>65 years) subjects compared to younger adult subjects (18 to 64
years). There was no detectable age effect, however, in the population pharmacokinetic
analysis in schizophrenia patients. Also, the pharmacokinetics of aripiprazole
after multiple doses in elderly patients appeared similar to that observed in
young, healthy subjects. No dosage adjustment is recommended for elderly patients
(see PRECAUTIONS: Geriatric Use).
Gender
Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole,
are 30 to 40% higher in women than in men, and correspondingly, the apparent
oral clearance of aripiprazole is lower in women. These differences, however,
are largely explained by differences in body weight (25%) between men and women.
No dosage adjustment is recommended based on gender.
Race
Although no specific pharmacokinetic study was conducted to
investigate the effects of race on the disposition of aripiprazole, population
pharmacokinetic evaluation revealed no evidence of clinically significant race-related
differences in the pharmacokinetics of aripiprazole. No dosage adjustment is
recommended based on race.
Smoking
Based on studies utilizing human liver enzymes in vitro,
aripiprazole is not a substrate for CYP1A2 and also does not undergo direct
glucuronidation. Smoking should, therefore, not have an effect on the pharmacokinetics
of aripiprazole. Consistent with these in vitro results, population pharmacokinetic
evaluation did not reveal any significant pharmacokinetic differences between
smokers and nonsmokers. No dosage adjustment is recommended based on smoking
status.
Drug-Drug Interactions
Potential for Other Drugs to Affect ABILIFY
Aripiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6,
CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. Aripiprazole also does not
undergo direct glucuronidation. This suggests that an interaction of aripiprazole
with inhibitors or inducers of these enzymes, or other factors, like smoking,
is unlikely.
Both CYP3A4 and CYP2D6 are responsible for aripiprazole metabolism.
Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole
clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or
CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit aripiprazole elimination
and cause increased blood levels.
Potential for ABILIFY to Affect Other Drugs
Aripiprazole is unlikely to cause clinically important pharmacokinetic
interactions with drugs metabolized by cytochrome P450 enzymes. In in vivo
studies, 10- to 30-mg/day doses of aripiprazole had no significant effect on
metabolism by CYP2D6 (dextromethorphan), CYP2C9 (warfarin), CYP2C19 (omeprazole,
warfarin), and CYP3A4 (dextromethorphan) substrates. Additionally, aripiprazole
and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated
metabolism in vitro (see PRECAUTIONS: Drug-Drug
Interactions).
Aripiprazole had no clinically important interactions with
the following drugs:
Famotidine: Coadministration of aripiprazole (given
in a single dose of 15 mg) with a 40-mg single dose of the H2 antagonist
famotidine, a potent gastric acid blocker, decreased the solubility of aripiprazole
and, hence, its rate of absorption, reducing by 37% and 21% the Cmax of aripiprazole
and dehydro-aripiprazole, respectively, and by 13% and 15%, respectively, the
extent of absorption (AUC). No dosage adjustment of aripiprazole is required
when administered concomitantly with famotidine.
Valproate: When valproate (500-1500 mg/day) and aripiprazole
(30 mg/day) were coadministered at steady state, the Cmax and AUC of aripiprazole
were decreased by 25%. No dosage adjustment of aripiprazole is required when
administered concomitantly with valproate.
Lithium: A pharmacokinetic interaction of aripiprazole
with lithium is unlikely because lithium is not bound to plasma proteins, is
not metabolized, and is almost entirely excreted unchanged in urine. Coadministration
of therapeutic doses of lithium (1200-1800 mg/day) for 21 days with aripiprazole
(30 mg/day) did not result in clinically significant changes in the pharmacokinetics
of aripiprazole or its active metabolite, dehydro-aripiprazole (Cmax and AUC
increased by less than 20%). No dosage adjustment of aripiprazole is required
when administered concomitantly with lithium.
Dextromethorphan: Aripiprazole at doses of 10
to 30 mg per day for 14 days had no effect on dextromethorphan’s O-dealkylation
to its major metabolite, dextrorphan, a pathway known to be dependent on CYP2D6
activity. Aripiprazole also had no effect on dextromethorphan’s N-demethylation
to its metabolite 3-methyoxymorphan, a pathway known to be dependent on CYP3A4
activity. No dosage adjustment of dextromethorphan is required when administered
concomitantly with aripiprazole.
Warfarin: Aripiprazole 10 mg per day for 14 days
had no effect on the pharmacokinetics of R- and S-warfarin or on the pharmacodynamic
end point of International Normalized Ratio, indicating the lack of a clinically
relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding
of highly protein-bound warfarin. No dosage adjustment of warfarin is
required when administered concomitantly with aripiprazole.
Omeprazole: Aripiprazole 10 mg per day for 15
days had no effect on the pharmacokinetics of a single 20-mg dose of omeprazole,
a CYP2C19 substrate, in healthy subjects. No dosage adjustment of omeprazole
is required when administered concomitantly with aripiprazole.
Clinical Studies
The efficacy of ABILIFY in the treatment of schizophrenia was
evaluated in four short-term (4- and 6-week), placebo-controlled trials of acutely
relapsed inpatients who predominantly met DSM-III/IV criteria for schizophrenia.
Three of the four trials were able to distinguish aripiprazole from placebo,
but one study, the smallest, did not. Three of these studies also included an
active control group consisting of either risperidone (one trial) or haloperidol
(two trials), but they were not designed to allow for a comparison of ABILIFY
and the active comparators.
In the three positive trials for ABILIFY, four primary measures
were used for assessing psychiatric signs and symptoms. The Positive and Negative
Syndrome Scale (PANSS) is a multi-item inventory of general psychopathology
used to evaluate the effects of drug treatment in schizophrenia. The PANSS positive
subscale is a subset of items in the PANSS that rates seven positive symptoms
of schizophrenia (delusions, conceptual disorganization, hallucinatory behavior,
excitement, grandiosity, suspiciousness/persecution, and hostility). The PANSS
negative subscale is a subset of items in the PANSS that rates seven negative
symptoms of schizophrenia (blunted affect, emotional withdrawal, poor rapport,
passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity/flow
of conversation, stereotyped thinking). The Clinical Global Impression (CGI)
assessment reflects the impression of a skilled observer, fully familiar with
the manifestations of schizophrenia, about the overall clinical state of the
patient.
In a 4-week trial (n=414) comparing two fixed doses of ABILIFY
(15 or 30 mg/day) and haloperidol (10 mg/day) to placebo, both doses of ABILIFY
were superior to placebo in the PANSS total score, PANSS positive subscale,
and CGI-severity score. In addition, the 15-mg dose was superior to placebo
in the PANSS negative subscale.
In a 4-week trial (n=404) comparing two fixed doses of ABILIFY
(20 or 30 mg/day) and risperidone (6 mg/day) to placebo, both doses of ABILIFY
were superior to placebo in the PANSS total score, PANSS positive subscale,
PANSS negative subscale, and CGI-severity score.
In a 6-week trial (n=420) comparing three fixed doses of ABILIFY
(10, 15, or 20 mg/day) to placebo, all three doses of ABILIFY were superior
to placebo in the PANSS total score, PANSS positive subscale, and the PANSS
negative subscale.
In a fourth study, a 4-week trial (n=103) comparing ABILIFY
in a range of 5 to 30 mg/day or haloperidol 5 to 20 mg/day to placebo, haloperidol
was superior to placebo, in the Brief Psychiatric Rating Scale (BPRS), a multi-item
inventory of general psychopathology traditionally used to evaluate the effects
of drug treatment in psychosis, and in a responder analysis based on the CGI-severity
score, the primary outcomes for that trial. ABILIFY was only significantly different
compared to placebo in a responder analysis based on the CGI-severity score.
Thus, the efficacy of 15-mg, 20-mg, and 30-mg daily doses was
established in two studies for each dose, whereas the efficacy of the 10-mg
dose was established in one study. There was no evidence in any study that the
higher dose groups offered any advantage over the lowest dose group.
An examination of population subgroups did not reveal any clear
evidence of differential responsiveness on the basis of age, gender, or race.
A longer-term trial enrolled 310 inpatients or outpatients
meeting DSM-IV criteria for schizophrenia who were, by history, symptomatically
stable on other antipsychotic medications for periods of 3 months or longer.
These patients were discontinued from their antipsychotic medications and randomized
to ABILIFY 15 mg or placebo for up to 26 weeks of observation for relapse. Relapse
during the double-blind phase was defined as CGI-Improvement score of =5 (minimally
worse), scores =5 (moderately severe) on the hostility or uncooperativeness
items of the PANSS, or =20% increase in the PANSS total score. Patients receiving
ABILIFY 15 mg experienced a significantly longer time to relapse over the subsequent
26 weeks compared to those receiving placebo.
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