Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

Mechanism of action
It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D 2 and serotonin 5HT 1a receptors and R   R               R   R


 antagonism of serotonin 5HT 2a receptors. Aripiprazole exhibited antagonist properties in animal R   R


 models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D 2 and D 3 , serotonin R   R       R   R



5HT 1a and 5HT 2a receptors and moderate affinity for dopamine D 4 , serotonin 5HT 2c and 5HT 7 , R      R          R   R                              R   R                   R   R                  R   R 

 alpha-1 adrenergic and histamine H 1 receptors. Aripiprazole also exhibited moderate binding affinity R   R


 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 11 C-raclopride, a D 2 /D 3 receptor ligand, to the P   P               R   R   R   R


 caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety
Schizophrenia
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

A ripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult  28T         28T


 patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantly higher for patients on aripiprazole (43 %) than for haloperidol (30 %). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a significant improvement over haloperidol.

In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34 % in aripiprazole group and 57 % in placebo.

Weight gain
In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included
314 adult patients and where the primary end-point was weight gain, significantly less patients had at least 7 % weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on aripiprazole (n = 18, or 13 % of evaluable patients), compared to olanzapine (n = 45, or 33 % of evaluable patients).

Lipid parameters
In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL.
-Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (≥ 6.22 mmol/l) was 2.5 % for aripiprazole and 2.8 % for placebo and mean change from baseline was -0.15 mmol/l (95 % CI: -0.182, -0.115) for aripiprazole and -0.11 mmol/l (95 % CI: -0.148, -0.066) for placebo.
-Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (≥ 2.26 mmol/l) was 7.4 % for aripiprazole and 7.0 % for placebo and mean change from baseline was -
0.11 mmol/l (95 % CI: -0.182, -0.046) for aripiprazole and -0.07 mmol/l (95 % CI: -0.148, 0.007) for placebo.
-HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4 % for aripiprazole and 12.5 % for placebo and mean change from baseline was -0.03 mmol/l (95 % CI: -0.046, -0.017) for aripiprazole and -0.04 mmol/l (95 % CI: -0.056, -0.022) for placebo.
-Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (≥ 4.14 mmol/l) was 0.6 % for aripiprazole and 0.7 % for placebo and mean change from baseline was -0.09 mmol/l (95 % CI: -0.139, -0.047) for aripiprazole and -0.06 mmol/l (95 % CI: -0.116, -0.012) for placebo.

Prolactin
Prolactin levels were evaluated in all trials of all doses of aripiprazole (n = 28,242). The incidence of hyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3 %) was similar to that of placebo (0.2 %). For patients receiving aripiprazole, the median time to onset was 42 days and median duration was 34 days.
The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was 0.4 %, compared with 0.02 % for patients treated with placebo. For patients receiving aripiprazole, the median time to onset was 30 days and median duration was 194 days.

Manic episodes in Bipolar I Disorder
In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course.

In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo.

In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12.

In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy.

In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomization, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression.

In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Y-MRS and MADRS total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46 % decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65 % decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure, CGI-BP Severity of Illness score (mania). In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16 % in aripiprazole + lithium and 18 % in aripiprazole + valproate compared to 45 % in placebo + lithium and 19 % in placebo + valproate.
 in aripiprazole + lithium and 18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

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.

Biotransformation

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.

Elimination

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 [ 14 C]-labelled aripiprazole, approximately 27 % of the administered P   P


 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.

Pharmacokinetics in special patient groups

Elderly
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.

Gender
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.

Smoking
Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from 28T


 smoking on the pharmacokinetics of aripiprazole.
28T



Race
Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.

Renal impairment
The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects.

Hepatic impairment
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.