Chemical formula: C₂₃H₂₇Cl₂N₃O₂ Molecular mass: 448.385 g/mol PubChem compound: 60795
It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism of serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.
Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.
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.
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.
Aripiprazole is extensively metabolised by the liver 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 catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.
The total body clearance of aripiprazole is 0.7 ml/min/kg, which is primarily hepatic.
Following a single oral dose of [14C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.
The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights.
There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients.
There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients.
Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole.
Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.
The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects.
A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.
Administration of aripiprazole solution for injection was well tolerated and produced no direct target organ toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and 5 times, respectively, human exposure at the maximum recommended human dose of 30 mg intramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed at maternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose.
An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m²). However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility.
In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions on development.
Based on results of a full range of standard genotoxicity tests, aripiprazole was considered nongenotoxic. Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.
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