Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12 
Mechanism of action

It has been proposed that aripiprazole’s efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties of dopaminergic hypoactivity. Aripiprazole exhibits high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and has 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 cholinergic muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.


Aripiprazole oral 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.

Clinical efficacy and safety

Maintenance treatment of schizophrenia in adults
The efficacy of Abilify Maintena in the maintenance treatment of patients with schizophrenia was established in two randomised, double-blind, long-term trials.

The pivotal trial was a 38 week, randomised, double-blind, active-controlled trial designed to establish the efficacy, safety, and tolerability of this medicinal product administered as monthly injections compared to once daily oral aripiprazole tablets 10-30 mg as maintenance treatment in adult patients with schizophrenia. This trial consisted of a screening phase and 3 treatment phases: Conversion Phase, Oral Stabilisation Phase, and Double-blind, Active- controlled Phase.

Six-hundred and sixty two patients eligible for the 38-week Double-blind, Active-controlled Phase were randomly assigned in a 2:2:1 ratio to double-blind treatment to one of 3 treatment groups: 1) Abilify Maintena 2) the stabilisation dose of oral aripiprazole 10-30 mg, or 3) aripiprazole Long-Acting Injectable 50 mg/25 mg. The aripiprazole Long-Acting Injectable 50 mg/25 mg dose was included as a low dose aripiprazole to test assay sensitivity for the non-inferiority design.
The results of analysis of the primary efficacy endpoint, the estimated proportion of patients experiencing impending relapse by end of Week 26 of the Double-blind, Active-controlled Phase, showed that Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10-30 mg.
The estimated relapse rate by end of Week 26 was 7.12 % for Abilify Maintena, and 7.76 % for oral aripiprazole tablets 10-30 mg, a difference of -0.64 %.
The 95 % CI (-5.26, 3.99) for the difference in the estimated proportion of patients experiencing impending relapse by end of Week 26 excluded the predefined non-inferiority margin, 11.5 %. Therefore, Abilify Maintena is non-inferior to aripiprazole oral tablets 10-30 mg.

The estimated proportion of patients experiencing impending relapse by end of Week 26 for Abilify Maintena was 7.12 %, which was statistically significantly lower than in aripiprazole Long-Acting Injectable 50 mg/25 mg (21.80 %; p = 0.0006). Thus, superiority of Abilify Maintena over the aripiprazole Long-Acting Injectable 50 mg/25 mg was established and the validity of the trial design was confirmed.

The Kaplan-Meier curves of the time from randomisation to impending relapse during the 38-week, Double-blind , Active-controlled Phase for Abilify Maintena, oral aripiprazole 10-30 mg, and aripiprazole Long-Acting Injectable 50 mg/25 mg are shown in Figure 1.

Figure 1   Kaplan-Meier Product Limit Plot for Time to Exacerbation of Psychotic Symptoms/Impending Relapse


ARIP IMD 400/ 300 mg



Proportion of subjects free of impending relapse
ARIP 10-30 mg
ARIP IMD 50/25 mg

1.0


0.8

0.6

0.4

Log-Rank Test
0.2   ARIP IMD 400/300 mg vs. ARIP 10-30 mg: p value 0.9920
ARIP IMD 400/300 mg vs. ARIP IMD 50/25 mg: p value < 0.0001

0.0
Numbers of Subjects at Risk
IMD 400/ 300 mg
ARIP 10-30 mg
IMD 50/25 mg


Days from Randomization

NOTE: ARIP IMD 400/300 mg = Abilify Maintena;ARIP 10-30 mg = oral aripiprazole; ARIP IMD 50/25 mg = Long-acting Injectable

Further, the non-inferiority of Abilify Maintena compared to oral aripiprazole 10-30 mg is supported by the results of the analysis of the Positive and Negative Syndrome Scale score (PANSS).

Table 1                                         PANSS Total Score – Change From Baseline to Week 38-LOCF: Randomised Efficacy Sample a, b

PANSS Total Score – Change From Baseline to Week 38-LOCF:
Randomised Efficacy Sample a, b
Abilify        Oral aripiprazole      Aripiprazole Long-Acting
Maintena                                 Injectable 50 mg/25 mg
400 mg/300 mg         10-30 mg/day
(n = 263)             (n = 266)                  (n = 131)
Mean baseline (SD)        57.9 (12.94)         56.6 (12.65)               56.1 (12.59) Mean change (SD)          -1.8 (10.49)          0.7 (11.60)                3.2 (14.45) P-value                       NA                  0.0272                     0.0002 a: Negative change in score indicates improvement.
b: Only patients having both baseline and at least one post baseline were included. P-values were derived from comparison for change from baseline within analysis of covariance model with treatment as term and baseline as covariate.

The second trial was a 52-week, randomised, withdrawal, double-blind, trial conducted in US adult patients with a current diagnosis of schizophrenia. This trial consisted of a screening phase and 4 treatment phases: Conversion, Oral Stabilisation, Abilify Maintena Stabilisation, and Double-blind Placebo-controlled. Patients fulfilling the oral stabilisation requirement in the Oral Stabilisation Phase were assigned to receive, in a single-blind fashion, Abilify Maintena and began an Abilify Maintena Stabilisation Phase for a minimum of 12 weeks and a maximum of 36 weeks. Patients eligible for the Double-blind, Placebo-controlled Phase were randomly assigned in a 2:1 ratio to double-blind treatment with Abilify Maintena or placebo, respectively.
The final efficacy analysis included 403 randomised patients and 80 exacerbations of psychotic symptoms/impending relapse events. In the placebo group 39.6% of the patients had progressed to impending relapse, whilst in the Abilify Maintena group impending relapse occurred in 10% of the patients; thus patients in the placebo group had a 5.03-fold greater risk of experiencing impending relapse.


Prolactin
In the Double-blind Active-controlled Phase of the 38-week trial, from baseline to last visit there was a mean decrease in prolactin levels in Abilify Maintena (−0.33 ng/ml) compared with a mean increase in oral aripiprazole tablets 10-30 mg (0.79 ng/ml; p < 0.01). The incidence of Abilify Maintena patients with prolactin levels > 1 time the upper limit of normal range (ULN) at any assessment was 5.4 % compared with 3.5 % of the patients on oral aripiprazole tablets 10-30 mg. Male patients generally had a higher incidence than female patients in each treatment group.

In the Double-blind Placebo-controlled Phase of the 52-week trial, from baseline to last visit there was a mean decrease in prolactin levels in Abilify Maintena (−0.38 ng/ml) compared with a mean increase in placebo (1.67 ng/ml). The incidences of Abilify Maintena patients with prolactin levels > 1 time the upper limit of normal range (ULN) was 1.9 % compared to 7.1 % for placebo patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Aripiprazole absorption into the systemic circulation is slow and prolonged following Abilify Maintena administration due to low solubility of aripiprazole particles.

The average absorption half-life of Abilify Maintena is 28 days. Absorption of aripiprazole from the IM depot formulation was complete relative to the IM standard (immediate-release) formulation. The dose adjusted Cmax values for the depot formulation were approximately 5% of Cmax from IM standard formulation.

Following a single dose administration of Abilify Maintena in the deltoid and gluteal muscle, the extent of absorption (AUC) was similar for both injection sites, but the rate of absorption (Cmax) was higher following administration to the deltoid muscle.

Following multiple intramuscular doses, the plasma concentrations of aripiprazole gradually rise to a maximum plasma concentration at a median tmax of 7 days for the gluteal muscle and 4 days for the deltoid muscle.

Steady state concentrations for the typical subject were attained by the fourth dose for both sites of administration.

Less than dose-proportional increases in aripiprazole and dehydro-aripiprazole concentrations and AUC parameters are observed after monthly Abilify Maintena injections of 300 mg to 400 mg.

Distribution
Based on results from trials with oral administration 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.

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. After multiple dose administration of Abilify Maintena, dehydro-aripiprazole, the active metabolite, represents about 29.1-32.5 % of aripiprazole AUC in plasma.

Elimination

After administration of multiple dose of 400 mg or 300 mg of Abilify Maintena, the mean aripiprazole terminal elimination half-life is respectively 46.5 and 29.9 days presumably due to absorption rate-limited kinetics.
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.

Pharmacokinetics in special patient groups

CYP2D6 poor metabolisers
Based on population pharmacokinetic evaluation of Abilify Maintena, the total body clearance of aripiprazole was 3.71 L/h in extensive metabolisers of CYP2D6 and approximately 1.88 L/h (approximately 50 % lower) in poor metabolisers of CYP2D6 (for dose recommendation, see section 4.2).

Elderly
After oral administration of aripiprazole, there are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects. Similarly, there was no detectable effect of age in a population pharmacokinetic analysis of Abilify Maintena in schizophrenia patients.

Gender
After oral administration of aripiprazole, there are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects. Similarly, there was no clinically relevant effect of gender in a population pharmacokinetic analysis of Abilify Maintena in clinical trials in patients with schizophrenia.

Smoking
Population pharmacokinetic evaluation of oral aripiprazole has revealed no evidence of clinically relevant effects from smoking on the pharmacokinetics of aripiprazole.

Race

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

Renal impairment
In a single-dose study with oral administration of aripiprazole, the pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to that in young healthy subjects.

Hepatic impairment
A single-dose study with oral administration of aripiprazole to 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.