Pharmacology: Mechanism of Action: The mechanism of action of aripiprazole, as with other drugs having efficacy in Schizophrenia and agitation associated with 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 (e.g., the orthostatic hypotension observed with aripiprazole may be explained by its antagonist activity at adrenergic alpha1 receptors).
Pharmacodynamics: Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1A and 5- HT2A receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, 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 nM, 15 nM, 39 nM, 57 nM, 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.
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 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.
Pharmacokinetic studies showed that Aripiprazole Orally Disintegrating Tablets are bioequivalent to Aripiprazole Tablets.
Absorption: Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole.
Distribution: Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.
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 aripiprazole with known inhibitors of CYP2D6, such as quinidine or fluoxetine in EMs, approximately doubles aripiprazole plasma exposure, and dose adjustment is needed. The mean elimination 50 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 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 dose was recovered unchanged in the feces.