The Pharmacology and Toxicology of Aripiprazole

Michael Levine, BA1
Stephen Traub, MD2
Michael J Burns, MD, FACEP, FACMT2

Authors Affiliations:
1 Finch University and the Chicago Medical School. North Chicago, IL 60607
2 Division of Medical Toxicology. Department of Emergency Medicine CC2, Beth Israel Deaconess Medical Center, One Deaconess Road, Boston MA., 02215

Corresponding author:
Michael J Burns, MD
Division of Medical Toxicology
Department of Emergency Medicine CC2
Beth Israel Deaconess Medical Center
One Deaconess Road
Boston, MA 02215
Phone: (617) 754-2326
Fax: (617) 754-2350

Int J Med Toxicol 2004; 7(1): 5

There are no financial, litigational, or other relationships that may lead to conflict of interest, particularly with Bristol-Meyers Squibb, the manufacturer of Aripiprazole (AbilifyTM )

The introduction of the first antipsychotic agents (e.g., chlorpromazine and haloperidol) in the early 1950s revolutionized the treatment of schizophrenia.  Whereas drug therapy for schizophrenia had previously involved the nonspecific use of sedatives (e.g., barbiturates) to calm patients during episodes of agitation, antipsychotic therapy provided specific and effective control of the positive signs and symptoms (e.g., delusions, disorganized behavior, and hallucinations) of schizophrenia through dopamine D2 neuroreceptor blockade.  Shortly after their introduction, traditional antipsychotic agents were noted to produce disabling neuroleptic or extrapyramidal side effects (EPS) and adverse neuroendocrine effects from hyperprolactinemia.(1,2)  In addition, these agents were limited by their lack of efficacy for treating the negative signs and symptoms (e.g., alogia, avolition, social withdrawal, and flattened affect) and neurocognitive deficits of schizophrenia. 

The need for antipsychotic agents with improved efficacy and side effect profiles led to the development of the second-generation, or atypical, antipsychotic agents during the 1990s.  These agents are less tightly bound to the D2 receptor and combine D2 receptor antagonism with antagonism at serotonin 5-HT2 receptors.(2)  Currently, five such agents are available for clinical use in the United States: clozapine, olanzapine, quetiapine, risperidone, and ziprasidone.  Unlike traditional antipsychotics, these agents produce minimal EPS at clinically effective antipsychotic doses and appear effective for treating the negative signs and symptoms and neurocognitive deficits of schizophrenia.  Atypical agents, however, produce a variety of adverse effects that have limited efficacy and patient compliance.  These adverse effects include somnolence, weight gain, glucose intolerance, dyslipidemia, increased QTc interval, and myocarditis.(2-4)  There is ongoing need for the development of antipsychotic agents that further enhance efficacy, minimize side effects, and improve patient compliance.

In 2002, aripiprazole became the newest atypical antipsychotic agent to receive approval by the Food and Drug Administration (FDA).(5,6)  As a serotonin and dopamine system stabilizer, it belongs to a new class or third-generation of antipsychotics.(7,8)  The following is a description of the pharmacology, pharmacokinetics, and predicted toxicology of aripiprazole. 

Structure And Pharmacology
Aripiprazole (7-{4-[4-(2,3 dichlorophenyl)-1-piperazinyl]butyloxy}-3,4-dihydro-2(1H)-quinolinone; OPC-14597) is a heterocyclic quinolinone derivative with a unique neuroreceptor binding profile (see figure 1 ).(9-11) Aripiprazole (AbilifyTM) is co-marketed by Bristol-Myers Squibb and Otsuka Pharmaceutical Company, Inc.(5,6) It is clinically available in the United States, Japan, Brazil, and Mexico.

Aripiprazole has a mechanism of action that differs from all currently available typical and atypical antipsychotic agents. Aripiprazole is a high-affinity, partial agonist of the dopamine D2 receptor.(9,10) As a partial agonist, aripiprazole functions as a dopamine system stabilizer, reducing dopaminergic neurotransmission when such activity is excessive and enhancing it when such activity is deficient. This restores dopamine neurotransmission to the normal range.5,7,8,12 As a partial agonist of the 5-HT1A receptor and an antagonist of the 5-HT2A receptor, aripiprazole could be considered a serotonin system stabilizer as well.11,13 The favorable therapeutic and side effect profile of aripiprazole (e.g., efficacy for both the positive and negative signs and symptoms of schizophrenia and lower incidence of EPS, prolactin elevation, and weight gain) is likely mediated by its partial agonist activity at D2 and 5-HT1A receptors and its antagonist activity at 5-HT2 receptors.(5,12,14,15)

Aripiprazole also binds with high affinity to dopamine D3 receptors.(16-18) It binds with moderate affinity to dopamine D4, serotonin 5-HT2C and 5-HT7, alpha1-adrenergic, and histamine H1 receptors, and the serotonin reuptake site. (16-18) It has no appreciable affinity for cholinergic muscarinic receptors. (16-18)

Aripiprazole is available in 5-, 10-, 15-, 20-, and 30-mg tablets. (5,6,16) The manufacturer recommends a starting adult dose of 10- or 15-mg once daily.(16) Higher doses have not been more effective.(6,16) Aripiprazole is well-absorbed from the gastrointestinal (GI) tract with a mean bioavailability of 87%.(16) GI absorption of aripiprazole is slow; peak plasma concentration (Cmax) occurs 3 to 5 hours after ingestion.(12,16,19) Mean peak plasma aripiprazole concentrations range from 74 to 452 ng/mL for 5- to 30-mg doses, respectively.(19) Food delays the rate of, but does not alter the extent of, absorption.(16) When a 15-mg tablet of aripiprazole is consumed with a high-fat meal, neither the Cmax nor the area under the curve (AUC) were altered.(16) The time to peak plasma concentration (tmax), however, was delayed by three hours for aripiprazole, and by 12 hours for its principal metabolite, dehydro-aripiprazole.(16) Following absorption, aripiprazole is highly protein-bound (>99%) in the plasma, primarily to albumin, with a volume of distribution (Vd) of 4.9 L/kg.(16) To date, no therapeutic drug concentrations have been established. The mean elimination half-life (t1/2 elim) is 75 hours.(19)

Aripiprazole is extensively metabolized in the liver by the cytochrome P450 mixed function oxidase system, predominantly by CYP3A4 and CYP2D6.(16) These isoenzymes metabolize aripiprazole to dehydro-aripiprazole, which is pharmacologically active and accounts for 40% of the parent drug's AUC in plasma at steady-state.(16) A small amount of aripiprazole is excreted unchanged in the urine (1%) and feces (18%).(16)

Special Populations
No dosage adjustment is recommended by the manufacturer on the basis of a patient's age, gender, race, smoking status, and hepatic or renal function (16,20-23) Although AUC measurements for patients with hepatic and renal impairment are generally higher than healthy subjects, these differences are not large enough to require dose adjustment.(16-21) 

A minority of the population (approximately 7 percent of Caucasians, 2 percent of African Americans, and less than 1 percent of Asians) have reduced activity of the CYP2D6 isoenzyme system and are considered CYP2D6 poor metabolizers (PM); the rest of the population are extensive metabolizers (EM).  For a given dose of aripiprazole, PM  individuals have an approximately 80% increase and 30% decrease in exposure (AUC) to aripiprazole and dehydro-aripiprazole, respectively, as compared to EM subjects.(16)  This constitutes a significantly higher exposure (60%) to the total active moieties in PM as compared to EM individuals.(16)  The mean elimination t1/2 for PM subjects is approximately double that for EM individuals (146 versus 75 hours, respectively).(16)  Thus, dose adjustment might be prudent if a patient were known to be a PM prior to drug initiation. 

Aripiprazole is classified as Pregnancy Category C.  Aripiprazole is associated with developmental toxicity and possible teratogenic effects in rats and rabbits.(16)  There are no studies evaluating aripiprazole in pregnant humans.  Aripiprazole is excreted in the milk of rats during lactation but it is unknown if aripiprazole or its metabolites are excreted in human milk.(16)  The manufacturer recommends that aripiprazole should not be used in lactating women.(16) 

Pediatric and adolescent patients have used aripiprazole safely.(22,23)

Drug Interactions
Repeated administration of aripiprazole at doses of 10- to 30-mg has not been associated with induction or inhibition of the CYP3A4 and CYP2D6 isoenzymes; aripiprazole is not known to affect the metabolism of other drugs.(16) The metabolism of aripiprazole, however, is affected by drugs that alter CYP3A4 and CYP2D6 activity.  Agents that induce CYP3A4 , such as carbamazepine, could increase the clearance of aripiprazole and lower serum concentrations of the drug.(16)  Conversely, drugs that inhibit the CYP3A4 isoenzyme, such as erythromycin and ketoconazole, as well as inhibitors of the CYP2D6 isoenzyme, such as quinidine or fluoxetine may decrease aripiprazole elimination, resulting in increased serum concentrations of aripiprazole and dehydro-aripiprazole.(16)  Co-administration of aripiprazole with quinidine results in a 112% increase in plasma exposure to aripiprazole.(16)  The manufacturer recommends that the dose of aripiprazole should be halved and doubled when co-administered with CYP2D6 and CYP3A4 inhibitors and inducers, respectively.(16) 

There is the potential for clinically significant pharmacodynamic interactions occurring with aripiprazole.  Since aripiprazole has some alpha1-adrenergic and H1 receptor antagonism, the ability to potentiate the effects of certain antihypertensive and antihistamine agents exists.  In addition, the co-administration of aripiprazole with other central nervous system depressants may produce additive or synergistic sedating effects.(16)  Such interactions, however, have not yet been reported.

Clinical Efficacy
Aripiprazole has been compared with placebo, haloperidol, risperidone, and olanzapine in numerous double-blind studies lasting from four weeks to one year.(24-32)  In general, aripiprazole has demonstrated superior efficacy when compared to placebo and similar efficacy when compared to other antipsychotics.  Like other antipsychotics, aripiprazole has also been shown to be significantly more effective than placebo for the management of acute mania.(33) In nearly all studies to date, aripiprazole appeared to be no more likely than placebo to induce sedation, anticholinergic effects, EPS, weight gain, electrocardiogram (ECG) changes, or to increase serum prolactin.(24-34) 

Toxicology / Adverse Reactions
Animal toxicity data.  Detailed animal toxicity data is not available from the manufacturer other than that listed in the prescribing information (personal communication with Bristol Meyers-Squibb pharmaceuticals, October 2003).  The aripiprazole dose in pregnant rats that produces slight maternal toxicity is 30 mg/kg orally.(16)  Aripiprazole has produced retinal degeneration in albino rats treated with 40- to 60-mg/kg doses (approximately 200 times the recommended daily human dose) orally over a period from 26 to 104 weeks.(16)

One in vivo canine model studied the cardiohemodynamic and electrophysiological effects of intravenous aripiprazole in comparison to haloperidol at doses producing plasma concentrations approximately 10 times that recommended for humans.(35)  At the highest dose only, aripiprazole resulted in negative chronotropic and dromotropic effects, hypotension, and mild to moderate prolongation of the ventricular effective refractory period and repolarization phase.  The prolongation of the ventricular repolarization phase caused by aripiprazole was about one-fourth that caused by haloperidol.(35)  This animal data suggests that aripiprazole possesses mild cardiodepressive and potassium channel-blocking activity, which manifests at supratherapeutic concentrations of the drug.

Human Toxicity Data.  In premarketing trials, aripiprazole was evaluated for safety in 5592 patients, of which 1251 had at least one year of drug exposure.(16)  To date, aripiprazole has been well-tolerated with an adverse event and drug discontinuation incidence similar to that of placebo.  The most common adverse effects associated with the use of aripiprazole include headache, nausea, vomiting, constipation, insomnia, lightheadedness, and somnolence, anxiety, agitation, akathisia, and tremor.(16,20,29,31) In general, adverse events occur early in treatment, in less than one-third of patients, and with a similar frequency to that seen with placebo. (12,16,20) Somnolence is the only adverse effect that has demonstrated a dose-response relationship.  Somnolence was noted in 15.3% of patients taking 30-mg but 7.5% and 7.7% of patients taking 20-mg and placebo, respectively.(5,6,12,29)

Aripiprazole has a more favorable safety profile than haloperidol.  In a meta-analysis of short-term safety trials in schizophrenia, adverse events occurred with similar frequency in the aripiprazole (n=926) and placebo (n=413) groups, whereas an increased incidence of akathisia, somnolence, and EPS was noted in those patients treated with haloperidol (n=200).(29) 

Aripiprazole may have a more favorable safety profile than other atypical agents. In a meta-analysis of short-term safety trials in schizophrenia, aripiprazole was not associated with hyperprolactinemia, EPS, significant weight gain, hyperlipidemia, glucose intolerance, or increases in the QTc interval.(29)  Although aripiprazole is associated with a small mean increase in body weight (+0.71 kg for combined data) when compared to placebo, significant reductions in body weight along with a decrease in serum prolactin levels and EPS have been demonstrated when patients are switched to aripiprazole from olanzapine or risperidone.(5,29,36)  In a safety study meta-analysis, aripiprazole treatment was associated with a mean decrease in QTc interval at all doses (2-30 mg) and no dose-response relationship was observed between aripiprazole and the changes in QTc interval.(29,34)  In addition, there is no correlation between aripiprazole plasma level and the measured QTc interval.(5,12,29,34)  Many atypical agents (e.g., quetiapine, risperidone, ziprasidone) have been associated with dose-related QTc interval prolongation.

In short term studies on aripiprazole, there have been no reported abnormalities in routine serum chemistry, hematology, or urinalysis parameters.(29) In addition, fasting glucose, triglyceride, HDL, LDL, and total cholesterol measurements appear to be unchanged in patients taking aripiprazole.(16,29)    

Aripiprazole, like other antipsychotic drugs, may produce neuroleptic malignant syndrome (NMS).  In premarketing studies, there were two possible cases of NMS identified in patients taking aripiprazole.(16)

Overdose.  In one preclinical study, the safety and tolerability of supratherapeutic doses of aripiprazole (30 to 90 mg/day) was investigated in 40 patients over 15 days.(37) There was an increased incidence of akathisia and sinus tachycardia in those that ingested 90-mg/day but no discontinuation due to adverse events in these or other patients.(37)  Overall, there were no dose-dependent changes in weight, serum prolactin concentrations, and the electrocardiograms of patients.(37)

During preclinical studies involving more than 5500 patients, unintentional or intentional acute overdose of aripiprazole was reported in seven patients (personal communication with Bristol Meyers-Squibb pharmaceuticals, October 2003).(16)  The largest overdose was 180mg, which occurred in two patients.  Clinical manifestations included somnolence in both and spontaneous emesis in one.  There were no vital sign, electrocardiographic, or laboratory abnormalities noted in either patient.(16) An 18-month old patient  ingested 15-mg of aripiprazole and 2-mg of lorazepam.  This overdose was uneventful.(16) A single post-marketing case of unintentional overdose has been reported in a two-and-a-half year old child, who ingested 225 mg  (17.1mg/kg) of aripiprazole.(38)  The patient developed mild tachycardia and significant CNS depression, but no cardiovascular instability, respiratory distress, or ECG changes.  Clinical effects were evident within 1 hour of ingestion and persisted for more than one week.  Recovery was complete. 

Overdose Management
Diagnosis of aripiprazole overdose is based primarily on a positive history of ingestion coupled with suggestive physical findings, which include sedation, ataxia, and mild tachycardia.  Since there is a dose-dependent sedative effect, significant overdose is likely to result in moderate to severe depression in mental status.  Although drug levels may correlate with toxicity, they are not readily or rapidly available and are highly unlikely to alter the care of the poisoned patient.(5,12,37)

Treatment of aripiprazole overdose is supportive.  Since coma is the most likely serious manifestation of large aripiprazole overdose, the maintenance or establishment of an adequate airway, oxygenation, and ventilation are the most important aspects of treatment for those with severe toxicity.  An ECG and continuous cardiac monitoring should be performed on all patients with aripiprazole overdose to evaluate for interval abnormalities (e.g., QTc prolongation) and arrhythmias, respectively.(16) If ECG interval abnormalities are noted, cardiac monitoring should be continued until they have resolved or the patient has been observed for approximately 24 hours.

Gastrointestinal decontamination (a single dose of activated charcoal) should be initiated as soon as possible after patient presentation.  The administration of 50 grams of activated charcoal has been shown to reduce the mean AUC and Cmax of aripiprazole by 50% in human volunteers that have ingested a single 15-mg tablet.(16)  Based on aripiprazole pharmacokinetic data (large Vd and high degree of protein binding), multi-dose charcoal, hemodialysis, and hemoperfusion are unlikely to be effective in enhancing aripiprazole elimination, and are not recommended.

Aripiprazole is a novel atypical antipsychotic that stabilizes the dopamine and serotonin system through partial agonism at D2 and 5-HT1A receptors.  It appears to have similar therapeutic efficacy with a more favorable side effect profile than existing atypical antipsychotic agents.  Although experience is limited, aripiprazole overdose is likely to produce a graded degree of CNS depression, ataxia, and mild tachycardia.  Toxic effects should be evident within a couple of hours of acute ingestion and could be long-lasting, particularly in non-habituated patients, those at the extremes of age, or poor metabolizers at CYP2D6.  Supportive care coupled with single-dose activated charcoal is the mainstay of therapy for those with aripiprazole overdose.


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