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Pharmacology: Pharmacodynamics: 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 drug.
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).
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: 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 trials 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 1 as follows. Results for the secondary outcome parameter (CGI) and additional endpoints were supportive of the primary endpoint. (See Table 1.)
Click on icon to see table/diagram/imageEfficacy 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 trial 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 trial. 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 2). 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 2).
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. (See Table 2.)
Click on icon to see table/diagram/imageBipolar 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) including 492, 235 and 310 respectively, who met DSM-IV-TR criteria for bipolar I disorder with manic or mixed episodes with or without psychotic features. In all three trials, cariprazine was superior to placebo.
The 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.
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.
In one of the three placebo-controlled trial 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. In another placebo-controlled trial 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. In the third 3-week, placebo-controlled trial 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 and there was a dose-related increase in certain adverse reactions. Therefore, the maximum recommended dose is 6 mg/day. (See Table 3.)
Click on icon to see table/diagram/imageDepressive 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 fixed-dose placebo-controlled trials in patients (mean age of 41.6 years, range 18 to 65 years) including 571, 474 and 478 patients respectively, 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 secondary endpoint was change from baseline to Week 6 in CGI-S.
In the 8-week, placebo-controlled trial 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. In one of the 6-week, placebo-controlled trials, 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. In the other 6-week, placebo-controlled trial 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. (See Table 4.)
Click on icon to see table/diagram/imagePaediatric population: See Dosage & Administration for information on paediatric use.
Pharmacokinetics: 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, 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 feces.
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 Dosage & Administration).
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 (Cmax 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 Cmax) 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 Dosage & Administration).
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 Dosage & Administration). 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, CYP2C19, 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 Interactions).
Toxicology: Preclinical safety data: Cariprazine caused bilateral cataract and secondary retinal changes (retinal detachment and cystic degeneration) in the dog. The exposure (AUC of total cariprazine) at the no-observed-adverse-effect-level (NOAEL) for ocular toxicity is 4.2-fold the clinical AUC exposure at the maximal recommended human dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observed in albino rats in the 2-year study at clinically relevant exposures.
Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal gland cortex of dogs at clinically relevant exposures. Inflammation was observed in the lungs of dogs dosed for 1 year with a NOAEL at AUC exposures 2.7 (males) and 1.7 (females) times the clinical exposure at the MRHD. No inflammation was observed at the end of 2-month drug-free period at an exposure 4.2 times the clinical exposure at the MRHD; however, inflammation was still present at higher doses.
Hypertrophy of the adrenal gland cortex was observed at 4.1 times the clinical exposure at the MRHD in rats (females only) and at clinically relevant total cariprazine plasma concentrations in mice. In dogs, reversible hypertrophy/hyperplasia and vacuolation/vesiculation of the adrenal gland cortex were observed with a NOAEL 4.2 times the clinical exposure at the MRHD.
In female rats, lower fertility and conception indices were observed at clinically relevant exposures based on mg/m2 body surface area. No effects on male fertility were noted at exposures up to 4.8 times the clinical exposure at the MRHD.
Administration of cariprazine to rats during the period of organogenesis caused malformations, lower pup survival, and developmental delays at drug exposures less than the human exposure at the MRHD of 6 mg/day. In rabbits, cariprazine caused maternal toxicity, but no foetal toxicity at exposures 5.8 times the clinical exposure at the MRHD.
Administration of cariprazine to pregnant rats during the period of organogenesis, throughout pregnancy and lactation at clinically relevant exposures decreased postnatal survival, birth weight, and post-weaning body weight of first generation pups. In addition, pale, cold bodies and developmental delays (renal papillae not developed/underdeveloped and decreased auditory startle response in males) were observed in the absence of maternal toxicity. Reproductive performance of the first generation pups was unaffected; however, second generation pups also had similar clinical signs and lower body weight.
Cariprazine and its metabolites were excreted in milk of rats during lactation.
