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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, α1-adrenergic and histamine H1 receptors (Ki values of 44, 15, 39, 57 and 61 nM, respectively), and moderate affinity for the serotonin re-uptake 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 and bipolar disorder 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 α1-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 and 94 hrs 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 is dose-proportional. Elimination of aripiprazole is mainly through hepatic metabolism involving two P-450 isozymes, CYP2D6 and CYP3A4.
Absorption: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3-5 hrs; the absolute oral bioavailability of the tablet formulation is 87%. Abilify can be administered with or without food. Administration of a 15-mg 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 hrs for aripiprazole and 12 hrs for dehydro-aripiprazole.
Distribution: The steady-state volume of distribution of aripiprazole following IV administration is high (404 L or 4.9 L/kg), indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and its major metabolite are >99% bound to serum proteins, primarily to albumin. In healthy human volunteers administered with aripiprazole 0.5-30 mg/day 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 3 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. Co-administration of Abilify with known inhibitors of CYP2D6 eg, quinidine in EMs, results in a 112% increase in aripiprazole plasma exposure, and dosing adjustment is needed (see Interactions). The mean elimination half-lives are about 75 and 146 hrs 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 & Administration). The pharmacokinetics of aripiprazole in special populations are described as follows.
Hepatic Impairment (HI): In a single-dose study (aripiprazole 15 mg) 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 <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 (18-64 years). However, there was no detectable age effect 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 Increased Mortality in Elderly Patients with Dementia-Related Psychosis under Warnings and Use in the elderly under Precautions).
Gender: Cmax and AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30-40% 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. It also does not undergo direct glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or inducers of these enzymes or other factors eg, 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 P-450 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).
Aripiprazole had no clinically important interactions with the following drugs: Famotidine: Co-administration 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 co-administered 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 almost entirely excreted unchanged in urine. Co-administration 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 <20%). No dosage adjustment of aripiprazole is required when administered concomitantly with lithium.
Dextromethorphan: Aripiprazole at doses of 10-30 mg/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/day for 14 days had no effect on the pharmacokinetics of R- and S-warfarin or on the pharmacodynamic endpoint of international normalized ratio, indicating the lack of a clinically relevant effect of aripiprazole on CYP2C9 and CYP2C19 metabolism or the binding of a highly protein-bound warfarin. No dosage adjustment of warfarin is required when administered concomitantly with aripiprazole.
Omeprazole: Aripiprazole 10 mg/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: Schizophrenia: The efficacy of Abilify in the treatment of schizophrenia was evaluated in 4 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 4 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 (1 trial) or haloperidol (2 trials), but they were not designed to allow for a comparison of Abilify and the active comparators.
In the 3 positive trials for Abilify, 4 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 7 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 7 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 2 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 2 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 3 fixed doses of Abilify (10, 15 or 20 mg/day) to placebo, all 3 doses of Abilify were superior to placebo in the PANSS total score, PANSS positive subscale, and the PANSS negative subscale.
In a 4th study, a 4-week trial (n=103) comparing Abilify in a range of 5-30 mg/day or haloperidol 5-20 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, 20 and 30-mg daily doses was established in 2 studies for each dose, whereas the efficacy of the 10-mg dose was established in 1 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.
Bipolar Disorder: The efficacy of Abilify in the treatment of acute manic episodes was established in two 3-week, placebo-controlled trials in hospitalized patients who met the DSM-IV criteria for bipolar I disorder with manic or mixed episodes (in one trial, 21% of placebo and 42% of Abilify-treated patients had data beyond 2 weeks). These trials included patients with or without psychotic features and with or without a rapid-cycling course.
The primary instrument used for assessing manic symptoms was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance and insight) in a range from 0 (no manic features) to 60 (maximum score). A key secondary instrument included the Clinical Global Impression-Bipolar (CGI-BP) scale.
In the 2 positive 3-week, placebo-controlled trials (n=268; n=248) which evaluated Abilify 15 or 30 mg/day once daily (with a starting dose of 30 mg/day), Abilify was superior to placebo in the reduction of Y-MRS total score and CGI-BP severity of illness score (mania).
A trial was conducted in patients meeting DSM-IV criteria for bipolar I disorder with a recent manic or mixed episode who had been stabilized on open-label Abilify and who had maintained a clinical response for at least 6 weeks. The 1st phase of this trial was an open-label stabilization period in which inpatients and outpatients were clinically stabilized and then maintained on open-label Abilify (15 or 30 mg/day, with a starting dose of 30 mg/day) for at least 6 consecutive weeks. One hundred sixty-one (161) outpatients were then randomized in a double-blind fashion, to either the same dose of Abilify they were on at the end of the stabilization and maintenance period or placebo and were then monitored for manic or depressive relapse. During the randomization phase, Abilify was superior to placebo on time to the number of combined affective relapses (manic plus depressive), the primary outcome measure for this study. The majority of these relapses were due to manic rather than depressive symptoms. There is insufficient data to know whether Abilify is effective in delaying the time to occurrence of depression in patients with bipolar I disorder.
An examination of the population subgroups did not reveal any clear evidence of differential responsiveness on the basis of age and gender; however, there were insufficient numbers of patients in each of the ethnic groups to adequately assess intergroup differences.
Aripiprazole produced retinal degeneration in albino rats in a 26-week chronic toxicity study at a dose of 60 mg/kg and in a 2-year carcinogenicity study at doses of 40 and 60 mg/kg. The 40- and 60-mg/kg doses are 13 and 19 times the maximum recommended human dose (MRHD) based on mg/m2 and 7-14 times human exposure at MRHD based on AUC. Evaluation of the retinas of albino mice and monkeys did not reveal evidence of retinal degeneration. Additional studies to further evaluate the mechanism have not been performed. The relevance of this finding to human risk is unknown.
