Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX15 
Mechanism of action

The mechanism of action of cariprazine is not fully known. However the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at dopamine D3, D2 (Ki values of 0.085-0.3 nM versus 0.49-0.71 nM respectively) and serotonin 5-HT1A receptors (Ki values of 1.4- 2.6 nM), and antagonist activity at serotonin 5-HT2B, 5-HT2A and histamine H1 receptors (Ki values of
0.58-1.1 nM, 18.8 nM and 23.3 nM, respectively). Cariprazine has low affinity for serotonin 5-HT2C and adrenergic α1 receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no appreciable affinity for cholinergic muscarinic receptors (IC50 > 1000 nM). The two major active metabolites, desmethyl cariprazine and didesmethyl cariprazine have a similar in vitro receptor binding and functional activity profile as the parent active substance.

Pharmacodynamic effects

In vivo non-clinical studies demonstrated that cariprazine occupies D3 receptors to a similar extent as D2 receptors at pharmacologically effective doses. There was a dose-dependent occupancy of brain dopamine D3 and D2 receptors (with preferential occupancy in regions with higher D3 expression) in patients with schizophrenia within the therapeutic dose range of cariprazine for 15 days.

The effects of cariprazine on the QT interval were evaluated in patients with schizophrenia or schizoaffective disorder. Holter monitor-derived electrocardiographic assessments were obtained in 129 patients over a twelve hour period at baseline and steady state. No QT interval prolongation was detected following supratherapeutic doses (9 mg/day or 18 mg/day). No patients treated with cariprazine experienced QTc increases ≥ 60 msec from baseline, nor did any patient experience a QTc of > 500 msec in the study.

Clinical efficacy and safety

Schizophrenia
Efficacy with short-term use
The efficacy of cariprazine for the treatment of acute schizophrenia was studied in three multi-center, multinational, randomized, double-blind, placebo-controlled 6-week studies including 1,754 patients with the age of 18 to 60 years. The primary endpoint was change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score and the secondary endpoint was change from baseline to week 6 in the Clinical Global Impressions-Severity (CGI-S) score in all acute schizophrenia studies. In a multinational placebo controlled study using fixed doses of 1.5 mg, 3.0 mg and 4.5 mg cariprazine and 4.0 mg risperidone for assay sensitivity, all cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared 
to placebo. In another multinational placebo controlled study using fixed doses of 3.0 mg, and 6.0 mg cariprazine and 10 mg aripiprazole for assay sensitivity, both cariprazine doses and the active-control showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo. In a third multinational placebo controlled study using fixed/flexible doses of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both cariprazine doses groups showed statistically significant improvement in both primary as well as secondary endpoint compared to placebo.
Results for the primary outcome parameter are summarized in Table 6 below. Results for the secondary outcome parameter (CGI) and additional endpoints were supportive of the primary endpoint.

Table 6.    Change from baseline to week 6 in the PANSS total score in studies of acute exacerbations of schizophrenia—ITT population
Baseline      Change           Treatment difference versus
P-value
Mean ± SD LS mean (SE) placebo (95% CI)
PANSS total (MMRM)
RGH-MD-16 (n=711)
Placebo                     97.3 ± 9.22 –13.29 (1.82) —                                — Cariprazine 1.5 mg/day      97.1 ± 9.13 –21.27 (1.77) –7.97 (–12.94, –3.01)            0.0017 Cariprazine 3 mg/day        97.2 ± 8.66 –21.45 (1.74) –8.16 (–13.09, –3.22)            0.0013 Cariprazine 4.5 mg/day      96.7 ± 9.01 –23.77 (1.74) –10.48 (–15.41, –5.55)           < 0.0001 Risperidone 4 mg/day        98.1 ± 9.50 –29.27 (1.74) –15.98 (–20.91, –11.04)          < 0.0001* RGH-MD-04 (n=604)
Placebo                     96.5 ± 9.1 –14.3 (1.5)         —                           — Cariprazine 3 mg/day        96.1 ± 8.7 –20.2 (1.5)         –6.0 (–10.1, –1.9)          0.0044 Cariprazine 6 mg/day        95.7 ± 9.4 –23.0 (1.5)         –8.8 (–12.9, –4.7)          < 0.0001 Aripiprazole 10 mg/day      95.6 ± 9.0 –21.2 (1.4)         –7.0 (–11.0, –2.9)          0.0008* RGH-MD-05 (n=439)
Placebo                     96.6 ± 9.3 –16.0 (1.6)         —                           — Cariprazine 3 to 6 mg/day 96.3 ± 9.3 –22.8 (1.6)           –6.8 (–11.3, –2.4)          0.0029 Cariprazine 6 to 9 mg/day 96.3 ± 9.0 –25.9 (1.7)           –9.9 (–14.5, –5.3)          < 0.0001 CI = confidence interval; ITT = intent to treat; LS mean = least squares mean; PANSS = Positive and Negative Syndrome Scale.
*compared to placebo

Efficacy with long-term use
The efficacy of cariprazine for maintaining antipsychotic effect was investigated in a randomized- withdrawal, long-term clinical study. Totally, 751 patients with acute symptoms of schizophrenia received cariprazine 3-9 mg/day for 20 weeks, of whom 337 received cariprazine in the dose-range of 3 or 6 mg/day. Stabilized patients were then randomised to receive fixed doses of 3 or 6 mg cariprazine (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary outcome of the study was time to relapse. By the end of the study 49.0% of placebo-treated patients versus 21.6% of cariprazine-treated patients had a relapse of schizophrenic symptoms. Time to relapse (92 vs. 326 days- based on the 25th percentile) was therefore significantly longer in the cariprazine group than in the placebo group (p=0.009).

Efficacy in predominantly negative symptoms of schizophrenia
The efficacy of cariprazine for the treatment of predominantly negative symptoms of schizophrenia was investigated in a 26-week, multi-centre, double-blind, and active-controlled clinical study. Cariprazine (dose range 3-6 mg, target dose 4.5 mg) was investigated compared to risperidone (dose range 3-6 mg, target dose 4 mg) in patients with persistent, predominant negative symptoms of schizophrenia (n=461).
86% of patients were less than 55 years old, 54% of them were male.

Persistent predominant negative symptoms were defined as symptoms lasting for a period of at least 6 months with high level of negative symptoms and low level of positive symptoms [(PANSS factor 
score for negative symptoms ≥ 24, a score of ≥ 4 on a minimum 2 of the 3 PANSS items (N1: flat affect, N4: avolition, and N6: poverty of speech) and PANSS factor score for positive symptoms ≤ 19]. Patients with secondary negative symptoms, such as moderate to severe depressive symptoms and clinically relevant parkinsonism (EPS) were excluded.

Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the primary efficacy parameter, PANSS factor score for negative symptoms (PANSS-FSNS) (p< 0.001). However, a statistically significant difference (p=0.002) in favour of cariprazine over risperidone was observed from Week 14 onward (Table 7). Both cariprazine- and risperidone-treated patient groups have shown statistically significant improvement in the change from baseline for the secondary efficacy parameter, Personal and Social Performance (PSP) total score (p< 0.001). However, a statistically significant difference (p< 0.001) in favour of cariprazine over risperidone was observed from Week 10 onward (Table 7).
Differences on the Clinical Global Impression Severity (p=0.005) and Improvement (p<0.001) scales, as well as PANSS-FSNS response rates (PANSS FSNS ≥ 30% improvement at Week 26; p= 0.003) were supportive of findings on the primary and secondary efficacy parameters.

Table 7      Summary of results in study RGH-188-005

Efficacy parameter          Cariprazine     Risperidone      Estimated     95%CI         p-value LS mean         LS mean         treatment difference
PANSS-FSNS at
27.8            27.5             -           -              -
Baseline
PANSS-FSNS at Week
18.5            19.6             -           -              -
26
PANSS-FSNS CfB to                -8.9            -7.4           -1.5        -2,4; -       0.002 Week 26                                                                       0.5 Total PSP at Baseline            48.8            48.2             -            -            - Total PSP at Week 26             64.0            59.7             -            -            - Total PSP CfB to Week            14.3             9.7            4.6       2.7; 6.6      <0.001 26
CfB= change from baseline

Bipolar I disorder

Manic or mixed episodes associated with bipolar I disorder
The efficacy of cariprazine in the acute treatment of bipolar mania was established in three, 3-week placebo-controlled trials in patients (mean age of 39 years, range 18 to 65 years; 40% were female; and 48% were Caucasian) who met DSM-IV-TR criteria for bipolar 1 disorder with manic or mixed episodes with or without psychotic features. In all three trials, cariprazine was superior to placebo.
Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity scale (CGI-S) were used as the primary and secondary efficacy measures, respectively, for assessing psychiatric signs and symptoms in each trial:

• The YMRS is an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology. YMRS total score may range from 0 to 60 with a higher score reflecting greater severity.

• The CGI-S is validated clinician-related scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale.

In each study, the primary endpoint was decrease from baseline in YMRS total score at the end of week 3. The change from baseline for each cariprazine dose group was compared to placebo. The results of the trials are shown in Table 8. The time course of efficacy results is shown in Figure below.


Study 4: In a 3-week, placebo-controlled trial (N = 492) involving two flexible-dose range groups of cariprazine (3 to 6 mg/day or 6 to 12 mg/day), both cariprazine dose groups were superior to placebo on the YMRS total score and the CGI-S. The 6 to 12 mg/day dose group showed no additional advantage.

Study 5: In a 3-week, placebo-controlled trial (N = 235) involving a flexible-dose range of cariprazine (3 to 12 mg/day), cariprazine was superior to placebo on the YMRS total score and the CGI-S.

Study 6: In a 3-week, placebo-controlled trial (N = 310) involving a flexible-dose range of cariprazine (3 to 12 mg/day), cariprazine was superior to placebo on the YMRS total score and the CGI-S.

The efficacy of cariprazine was established at doses ranging from 3 to 12 mg/day. Doses above 6 mg did not appear to have additional benefit over lower doses (Table 8) and there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day.

Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness.

Table 8: Primary Analysis Results from Manic or Mixed Episodes Associated with Bipolar I Disorder Trials
Study     Treatment Group                   Primary Efficacy Endpoint: YMRS Total Number (# ITT patients)                  Mean          LS Mean        Placebo-subtracted Baseline      Change from Differencea (95% CI)
Score (SD)     Baseline (SE)

Study 4     Cariprazine (3-6 mg/day)*        33.2 (5.6)        -18.6 (0.8)         -6.1 (-8.4, -3.8) (n=165)
Cariprazine                      32.9 (4.7)        -18.5 (0.8)         -5.9 (-8.2, -3.6) (6-12 mg/day)*b
(n=167)
Placebo                          32.6 (5.8)        -12.5 (0.8)                -- 
(n=160)
Study 5     Cariprazine                        30.6 (5.0)       -15.0 (1.1)     -6.1 (-8.9, -3.3) (3-12 mg/day)*b
(n=118)
Placebo                            30.2 (5.2)        -8.9 (1.1)             -- (n=117)
Study 6 Cariprazine                            32.3 (5.8)       -19.6 (0.9)     -4.3 (-6.7, -1.9) (3-12 mg/day)*b
(n=158)
Placebo                            32.1 (5.6)       -15.3 (0.9)             -- (n=152)
ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval a
Difference (drug minus placebo) in least-squares mean change from baseline *Doses that are statistically significantly superior to placebo b
The maximum recommended daily dose is 6 mg. Doses above 6 mg daily do not confer increased effectiveness sufficient to outweigh dose-related adverse reactions.

Depressive Episodes Associated with Bipolar I Disorder (Bipolar Depression) 
The efficacy of cariprazine in the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) was established in one 8-week and two 6-week placebo-controlled trials in patients (mean age of 43 years, range 18 to 65 years; 61% were female; and 75% were Caucasian) who met DSM-IV-TR or DSM-5 criteria for depressive episodes associated with bipolar I disorder.

In each study, the primary endpoint was change from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at the end of Week 6. The MADRS is a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The MADRS total score change from baseline for cariprazine compared to placebo is shown in Table 9 below. The time course of efficacy results of Study 8 is shown in the below Figure. In each study, the cariprazine 1.5 mg dose demonstrated statistical significance over placebo. The secondary endpoint was change from baseline to Week 6 in CGIS.
The CGI-S is validated clinician-related scale that measures the patient’s current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale.

Study 7: In an 8-week, placebo-controlled trial (N = 571) involving three-fixed doses of cariprazine (0.75 mg/day, 1.5 mg/day, and 3 mg/day), cariprazine 1.5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S.

Study 8: In a 6-week, placebo-controlled trial (N = 474) involving two-fixed doses of cariprazine (1.5 mg/day and 3 mg/day), cariprazine 1.5 mg and 3 mg were superior to placebo at end of Week 6 on the MADRS total score.

Study 9: In a 6-week, placebo-controlled trial (N = 478) involving two-fixed doses of cariprazine (1.5 mg/day and 3 mg/day), cariprazine 1.5 mg was superior to placebo at end of Week 6 on the MADRS total score and the CGI-S.

Examination of population subgroups based on age (there were few patients over 55), sex, and race did not suggest any clear evidence of differential responsiveness.


Table 9: Primary Analysis Results from Bipolar Depression Trials
Study       Treatment Group (# ITT           Primary Efficacy Endpoint: MADRS Total Number      patients)                 Mean Baseline        LS Mean       Placebo-subtracted Score (SD)     Change from       Differencea (95%
Baseline (SE)             CI)
Study 7     Cariprazine (1.5 mg/day)*     30.3 (4.4)      -15.1 (0.8)      -4.0 (-6.3, -1.6) 
(n=145)

Cariprazine (3 mg/day)            30.6 (4.7)        -13.7 (0.9)          -2.5 (-4.9, -0.1) (n=145)
Placebo                           30.4 (4.6)        -11.1 (0.9)
(n=141)
Study 8    Cariprazine (1.5 mg/day)*         30.7 (4.3)        -15.1 (0.8)          -2.5 (-4.6, -0.4) (n=154)

Cariprazine (3 mg/day)*            31.0 (4.9)       -15.6 (0.8)     -3.0 (-5.1, -0.9) (n=164)
Placebo                            30.2 (4.4)       -12.6 (0.8)
(n=156)
Study 9 Cariprazine (1.5 mg/day)*              31.5 (4.3)       -14.8 (0.8)     -2.5 (-4.6, -0.4) (n=162)
Cariprazine (3 mg/day)             31.5 (4.8)       -14.1 (0.8)      -1.8 (-3.9, 0.4) (n=153)
Placebo                            31.4 (4.5)       -12.4 (0.8)
(n=163)
ITT: intent-to-treat; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval a
Difference (drug minus placebo) in least-squares mean change from baseline *Doses that are statistically significantly superior to placebo



Paediatric population
Cariprazine is not indicated for children and adolescents aged less than 18 years.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Cariprazine has two pharmacologically active metabolites with similar activities as cariprazine, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR). Total cariprazine (sum of cariprazine + DCAR and DDCAR) exposure approaches 50% of steady state exposure in ~1 week of daily dosing while 90% of steady state is achieved in 3 weeks. At steady state, exposure to DDCAR is approximately two to three-fold higher than to cariprazine, and exposure to DCAR is approximately 30% of cariprazine exposure.


Absorption

Absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oral administration. Following multiple-dose administration, peak plasma concentrations for cariprazine and the major active metabolites generally occur at approximately 3-8 hours post dose.
Administration of a single dose of 1.5 mg cariprazine with a high-fat meal (900 to 1,000 calories) did not significantly affect the Cmax or AUC of cariprazine (AUC0-∞ increased by 12%, Cmax decreased by < 5% under fed condition versus fasting). The effect of food on the exposure of the metabolites DCAR and DDCAR was also minimal.
Cariprazine can be administered with or without food.

Distribution

Based on a population pharmacokinetic analysis, the apparent volume of distribution (V/F) was 916 L for cariprazine, 475 L for DCAR and 1,568 L for DDCAR, indicating extensive distribution of cariprazine and its major active metabolites. Cariprazine and its major active metabolites are highly bound (96 to 97% for CAR, 94% to 97% for DCAR and 92% to 97% for DDCAR) to plasma proteins.

Biotransformation

The metabolism of cariprazine involves demethylation (DCAR and DDCAR), hydroxylation (hydroxy cariprazine, HCAR) and a combination of demethylation and hydroxylation (hydroxy desmethyl cariprazine, HDCAR and hydroxy didesmethyl cariprazine, HDDCAR). The metabolites of HCAR, HDCAR, and HDDCAR are subsequently biotransformed to their corresponding sulfate and glucuronide conjugates. An additional metabolite, desdichlorophenyl piperazine cariprazine (DDCPPCAR) acid, is produced by dealkylation and subsequent oxidation of cariprazine.
Cariprazine is metabolized by CYP3A4 and, to a lesser extent, by CYP2D6, to DCAR and HCAR.
DCAR is further metabolized by CYP3A4 and to a lesser extent by CYP2D6 into DDCAR and HDCAR.
DDCAR is further metabolised to HDDCAR by CYP3A4.

Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), the organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and OATP1B3), and the breast cancer resistance protein (BCRP). This suggests that an interaction of cariprazine with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP is unlikely.

Elimination

Elimination of cariprazine and its major active metabolites is mainly through hepatic metabolism.
Following administration of 12.5 mg/day cariprazine to patients with schizophrenia, 20.8% of the dose was excreted in urine as cariprazine and its metabolites.
Unchanged cariprazine is excreted by 1.2% of the dose in urine and 3.7% of the dose in faeces.

The mean terminal half-life (1 to 3 days for cariprazine and DCAR and 13 to 19 days for DDCAR) is not predictive of time to reach steady state or plasma concentration decline after treatment discontinuation. For the management of patients treated with cariprazine, the effective half-life is more relevant than the terminal half-life. The effective (functional) half-life is ~ 2 days for cariprazine and DCAR, 8 days for DDCAR and is ~1 week for total cariprazine. The plasma concentration of total cariprazine will gradually decline following dose discontinuation or interruption. The plasma concentration of total cariprazine decreases by 50% in ~1 week and greater than 90% decline in total cariprazine concentration occurs in ~3 weeks.

Linearity

After repeated administration plasma exposure of cariprazine and its two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR), increases proportionally over the therapeutic dose range of 1.5 to 6 mg.

Special populations

Renal impairment
Population pharmacokinetic modelling was performed using data from patients enrolled in the schizophrenia cariprazine clinical program with differing levels of renal function, including normal renal function (creatinine clearance (CrCl) ≥ 90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant relationship was found between cariprazine plasma clearance and creatinine clearance.
Cariprazine has not been evaluated in patients with severe (CrCl < 30 mL/min) renal impairment (see section 4.2).

Hepatic impairment
A 2-part study (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for 14 days [Part B] was conducted in patients with varying degrees of impaired hepatic function (Child- Pugh Classes A and B). Compared to healthy subjects, patients with either mild or moderate hepatic impairment had up to approximately 25% higher exposure (C max and AUC) for cariprazine and up to approximately 45% lower exposure for the major active metabolites, desmethyl cariprazine and didesmethyl cariprazine, following the single dose of 1 mg cariprazine or 0.5 mg cariprazine for 14 days.
The total active moiety (CAR+DCAR+DDCAR) exposure (AUC and C max) decreased by 21-22% and 13-15% in mild or moderate hepatic impairment (HI), respectively, compared to healthy subjects if unbound + bound concentrations were considered, while for unbound total moiety a decrease of 12-13% and an increase of 20-25% were calculated in mild HI patients and in moderate HI patients, respectively, after multiple dosing of cariprazine.
Cariprazine has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) (see section 4.2).

Age, gender and race
In the population PK analysis there were no clinically relevant differences in the PK parameters (AUC and Cmax of the sum of cariprazine and its major active metabolites) based on age, gender and race. This analysis included 2,844 patients of different races, involving 536 patients between the ages of 50 and 65. Of the 2,844 patients 933 were female (see section 4.2). In elderly patients above 65 years of age data are limited.

Smoking status
Because cariprazine is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of cariprazine.

Potential for cariprazine to affect other medicinal products

Cariprazine and its major active metabolites did not induce CYP1A2, CYP2B6 and CYP3A4 enzymes and were not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP219, CYP2D6, CYP2E1 and CYP3A4 in vitro. Cariprazine and its major active metabolites are not inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR were not inhibitors of transporter P-gp although cariprazine was a P-gp inhibitor in the intestine (see section 4.5).