Aripiprazole - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of aripiprazole in schizophrenia or bipolar mania, is unclear.

However, the efficacy of aripiprazole in the listed indications could be mediated through a combination of partial agonist activity at D 2 and 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors.

12.2 Pharmacodynamics Aripiprazole exhibits high affinity for dopamine D 2 and D 3 , serotonin 5-HT 1A and 5-HT 2A receptors (K i values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D 4 , serotonin 5-HT 2C and 5-HT 7 , alpha 1 -adrenergic and histamine H 1 receptors (K i values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (K i =98 nM).

Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC 50 >1000 nM).

12.3 Pharmacokinetics Aripiprazole 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 D 2 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 is dose-proportional.

Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.

For CYP2D6 poor metabolizers, the mean elimination half-life for aripiprazole is about 146 hours.

Oral administration Absorption Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%.

Aripiprazole can be administered with or without food.

Administration of a 15 mg aripiprazole tablet with a standard high-fat meal did not significantly affect the C max or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed T max 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 D 2 receptor occupancy indicating brain penetration of aripiprazole in humans.

Elimination Metabolism 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.