Out Of The Pipeline

IM aripiprazole for acute agitation

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Fast-acting injectable has shown efficacy 45 to 60 minutes after dosing in randomized, controlled studies.


 

References

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).1-3

Table 1

IM aripiprazole: Fast facts

Brand name: Abilify
Class: Second-generation antipsychotic
Indication: Acute agitation associated with schizophrenia or type I bipolar disorder (mixed or manic episodes)
Manufacturer: Otsuka America Pharmaceutical (marketed in collaboration with Bristol-Myers Squibb)
Dosing forms: 1.3-mL vial of clear, aqueous solution containing 9.75 mg of active drug
Recommended dosage: 9.75 mg every 2 hours as needed; do not exceed 30 mg across 24 hours

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.1-3

How it works

Whereas other SGAs have relatively little effect on D2 (dopamine) receptors and relatively high 5-HT2A (serotonin) receptor affinities, aripiprazole appears to work via partial D2 receptor agonism. The medication:

  • blocks D2 receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
  • maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT1A receptor agonist and—like other SGAs—a 5-HT2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT1A receptor agonism is thought to help:

  • reduce anxiety
  • lessen depressive, negative, and cognitive symptoms
  • decrease extrapyramidal symptom (EPS) liability.4

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D2 receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

  • agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
  • CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination9 and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al1followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al2followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

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