Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Aziende Chimiche Riunite Angelini Francesco – A.C.R.A.F. S.p.A., Viale Amelia 70, 00181, Rome Italy
Pharmacotherapeutic group: Psycholeptics, antipsychotics
ATC code: N05AE05
Lurasidone is a selective blocking agent of dopamine and monoamine effects. Lurasidone binds strongly to dopaminergic D2- and to serotonergic 5-HT2A- and 5-HT7- receptors with high binding affinity of 0.994, 0.47 and 0.495 nM, respectively. It also blocks α2c-adrenergic receptors and α2a-adrenergic receptors with a binding affinity of 10.8 and 40.7 nM respectively. Lurasidone also exhibits partial agonism at the 5-HT1A receptor with a binding affinity of 6.38 nM. Lurasidone does not bind to histaminergic or muscarinic receptors.
The mechanism of action of the minor active metabolite of lurasidone ID-14283 is similar to that of lurasidone.
Lurasidone doses ranging from 9 to 74 mg administered to healthy subjects produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate, putamen and ventral striatum detected by positron emission tomography.
In the main clinical efficacy studies, lurasidone was administered at doses of 37-148 mg lurasidone.
The efficacy of lurasidone in the treatment of schizophrenia was demonstrated in five multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia. Lurasidone doses, which varied across the five trials, ranged from 37 to 148 mg lurasidone once daily. In the short-term trials, the primary efficacy endpoint was defined as the mean change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total scores, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/excitement, and anxiety/depression. Lurasidone demonstrated superior efficacy compared with placebo across Phase 3 studies (see Table 2). Lurasidone showed significant separation from placebo from as early as Day 4. Additionally, lurasidone was superior to placebo on the predefined secondary endpoint Clinical Global Impression – Severity (CGI-S) scale. Efficacy was also confirmed in a secondary analysis of treatment response (defined as ≥30% decrease from Baseline in PANSS total score).
Table 3. Schizophrenia Adult Studies: Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score – Change from Baseline to Week 6 – MMRM for Studies D1050229, D1050231, and D1050233: Intent-to-Treat Analysis Set:
| Study Statistic | Placebo | Lurasidone doseb | Active controla | |||
|---|---|---|---|---|---|---|
| 37 mg | 74 mg | 111 mg | 148 mg | |||
| Study D1050229 | N=124 | N=121 | N=118 | N=123 | -- | -- |
| Baseline Mean (SD) | 96.8 (11.1) | 96.5 (11.6) | 96.0 (10.8) | 96.0 (9.7) | -- | -- |
| LS Mean Change (SE) | -17.0 (1.8) | -19.2 (1.7) | -23.4 (1.8) | -20.5 (1.8) | -- | -- |
| Treatment Difference vs. placebo | ||||||
| Estimate (SE) | -- | -2.1 (2.5) | -6.4 (2.5) | -3.5 (2.5) | -- | -- |
| p-value | -- | 0.591 | 0.034 | 0.391 | -- | -- |
| Study D1050231 | N=114 | N=118 | -- | N=118 | -- | N=121 |
| Baseline Mean (SD) | 95.8 (10.8) | 96.6 (10.7) | -- | 97.9 (11.3) | -- | 96.3 (12.2) |
| LS Mean Change (SE) | -16.0 (2.1) | -25.7 (2.0) | -- | -23.6 (2.1) | -- | -28.7 (1.9) |
| Treatment Difference vs. placebo | ||||||
| Estimate (SE) | -- | -9.7 (2.9) | -- | -7.5 (3.0) | -- | -12.6 (2.8) |
| p-value | -- | 0.002 | -- | 0.022 | -- | <0.001 |
| Study D1050233 | N=120 | -- | N=125 | -- | N=121 | N=116 |
| Baseline Mean (SD) | 96.6 (10.2) | -- | 97.7 (9.7) | -- | 97.9 (11.8) | 97.7 (10.2) |
| LS Mean Change (SE) | -10.3 (1.8) | -- | -22.2 (1.8) | -- | -26.5 (1.8) | -27.8 (1.8) |
| Treatment Difference vs. placebo | ||||||
| Estimate (SE) | -- | -- | -11.9 (2.6) | -- | -16.2 (2.5) | -17.5 (2.6) |
| p-value | -- | -- | <0.001 | -- | <0.001 | <0.001 |
a Olanzapine 15 mg in Study D1050231, quetiapine extended-release (XR) 600 mg in Study D1050233.
N is number of subjects per model estimate.
b p-values for lurasidone vs. placebo were adjusted for multiple comparisons. P-values for olanzapine and quetiapine XR vs. placebo were unadjusted.
In the short-term studies there was no consistent dose-response correlation observed.
Long-term maintenance efficacy of lurasidone (37 to 148 mg lurasidone once daily) was demonstrated in a 12 month non-inferiority trial with quetiapine extended release (200 to 800 mg once daily). Lurasidone was non-inferior to quetiapine extended release in time to relapse of schizophrenia. Lurasidone had a small increase from baseline to Month 12 in body weight and body mass index (Mean (SD): 0.73 (3.36) kg and 0.28 (1.17) kg/m², respectively) compared to quetiapine extended release (1.23 (4.56) kg and 0.45 (1.63) kg/m², respectively). Overall, lurasidone had a negligible effect on weight and other metabolic parameters including total cholesterol, triglycerides, and glucose levels.
In a long-term safety study clinically stable patients were treated using 37–111 mg lurasidone or risperidone 2–6 mg. In that study the rate of relapse over a 12-month period was 20% for lurasidone and 16% for risperidone. This difference neared, but did not reach, statistical significance.
In a long-term trial designed to assess the maintenance of effect, lurasidone was more effective than placebo in maintaining symptom control and delaying relapse of schizophrenia. After having been treated for an acute episode and stabilized for a minimum of 12 weeks with lurasidone, patients were then randomised in a double-blind manner to either continue on lurasidone or on placebo until they experienced a relapse in schizophrenia symptoms. In the primary analysis of time to relapse in which patients that withdrew without relapse were censored at the time of withdrawal, patients on lurasidone showed a significantly longer time to relapse compared with patients on placebo (p=0.039). The Kaplan-Meier estimates of the probability of relapse at Week 28 were 42.2% for lurasidone and 51.2% for placebo. The probability of all-cause discontinuation at Week 28 were 58.2% for lurasidone and 69.9% for placebo (p=0.072).
The efficacy of LATUDA, was established in a 6-week, randomized, double-blind, placebocontrolled study of adolescents (13 to 17 years) who met DSM-IV-TR criteria for schizophrenia (N=326). Patients were randomized to one of two fixed-doses of LATUDA (37 or 74 mg/day) or placebo.
The primary rating instrument used to assess psychiatric signs and symptoms was the PANSS. The key secondary instrument was the CGI-S.
For both dose groups, LATUDA was superior to placebo in reduction of PANSS and CGI-S scores at Week 6. On average, the 74 mg/day dose did not provide additional benefit compared to the 37 mg/day dose.
The primary efficacy results are provided in Table 4.
Table 4. Primary Efficacy Results (PANSS Total Score) - Change From Baseline to Week 6 – MMRM for the Adolescent Schizophrenia Study D1050301: Intent-to-Treat Analysis Set:
| Study Statistic | Placebo | Lurasidone dosea | |
|---|---|---|---|
| 37 mg | 74 mg | ||
| Study D1050301 | N=112 | N=108 | N=106 |
| Baseline Mean (SD) | 92.8 (11.08) | 94.5 (10.97) | 94.0 (11.12) |
| LS Mean Change (SE) | -10.5 (1.59) | -18.6 (1.59) | -18.3 (1.60) |
| Treatment Difference vs. placebo | |||
| Estimate (SE) | -- | -8.0 (2.21) | -7.7 (2.22) |
| p-value | -- | 0.0006 | 0.0008 |
N is number of subjects per model estimate.
a p-values for lurasidone vs. placebo were adjusted for multiple comparisons.
The improvements in the CGI-S scores at Week 6 were significantly different from placebo for both the lurasidone 74 mg/day (-0.42 ± 0.130, adjusted p=0.0015) and lurasidone 37 mg/day (-0.47 ± 0.130, adjusted p = 0.0008) treatment groups.
A 104-week extension study (Study D1050302) was designed to evaluate the long-term safety, tolerability, and effectiveness of flexibly dosed lurasidone (18.5, 37, 55.5, or 74 mg/day) in paediatric subjects who completed a 6-week treatment period in three preceding studies of various indications. Only results for 271 subjects with schizophrenia who enrolled from Study D1050301 are hereinafter presented. Of these, 186 subjects (68.6%) completed through 52 weeks and 156 (57.6%) subjects completed 104 weeks of flexible dosing with lurasidone 18.5 to 74 mg/day.
For subjects who continued from D1050301, the mean (95% CI) in PANSS total score from DB Baseline was-26.5 (-28.5, -24.5) at Week 28 LOCF, -28.2 (-30.2, -26.2) at Week52 LOCF, and -29.5 (-31.8, -27.3) at Week 104 LOCF/post-OL Endpoint, and mean change (95% CI) from OL Baseline was -9.2 (-11.1, -7.2) at Week 28 LOCF, -10.8 (-13.0, -8.7) at Week 52 LOCF, and -12.2 (-14.5, -9.8) at Week 104 LOCF/post-OL Endpoint, respectively.
The short-term efficacy of lurasidone was studied in a 6-week multicentre, randomized, double-blind, placebo-controlled, study of children and adolescent patients (10-17 years of age) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria for a major depressive episode associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=350). Patients were randomized to flexibly dosed lurasidone 18-74 mg once daily or placebo.
The primary efficacy endpoint was defined as the mean change from baseline to Week 6 in Children’s Depression Rating Scale, Revised (CDRS-R) Total Score. The key secondary endpoint was Clinical Global Impression – Bipolar Version, Severity of Illness (CGI-BP-S) Depression Score. Statistically significant differences favouring lurasidone over placebo were shown for these endpoints for the total population studied, beginning at Week 2 and were maintained at each study visit through to the end of the study. However, the primary and key secondary efficacy endpoints were not met in younger patients (below 15 years of age). Placebo-adjusted LS mean change (95% CI) from Baseline to Week 6 LOCF in CDRS-R total score for the lurasidone group was -1.8 (5.6, 2.0) for subjects in the 10 to 14-year-old age patients and was -8.6 (-12.4, 4.8) for subjects in the 15 to 17-year-old age patients (Table 5).
The safety profile of lurasidone in children included in this short-term study is in general consistent with that observed when treated within the approved indication in adults, however, differences in frequency of the most commonly occurred adverse reactions have been observed in paediatric patients for nausea (very common), diarrhea (common) and decreased appetite (common), compared with adults (common, unknown, and uncommon, respectively).
Table 5. Bipolar Depression Paediatric Study: Children’s Depression Rating Scale, Revised (CDRS-R) Total Score and Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) Depression Score (Depression) - Change From Baseline to Week 6 – MMRM for Study D1050326: Intent-to-Treat Analysis Set:
| Parameters | Study Statistic | Placebo | Lurasidone dose 18.5-74 mga,b |
|---|---|---|---|
| Primary Endpoint: CDRS-R Total Score | N=170 | N=173 | |
| Baseline Mean (SD) | 58.6 (8.26) | 59.2 (8.24) | |
| LS Mean Change (SE) | -15.3 (1.08) | -21.0 (1.06) | |
| Treatment Difference vs. placebo | |||
| Estimate (SE; 95% CI) | -- | -5.7 (1.39. -8.4 to -3.0) | |
| p-value | -- | <0.0001 | |
| Key Secondary Endpoint: | N=170 | N=173 | |
| Baseline Mean (SD) | 4.5 | 4.6 | |
| LS Mean Change (SE) | -1.05 (0.087) | -1.49 (0.085) | |
| Treatment Difference vs. placebo | |||
| Estimate (SE; 95% CI) | -- | -0.44 (0.112. -0.66 to -0.22) | |
| p-value | -- | <0.0001 |
N is number of subjects.
a p-values for lurasidone vs. placebo were adjusted for multiple comparisons.
b Lurasidone doses of 18.5, 37, 55.5, 74 mg are equivalent to 20, 40, 60 and 80 amounts of lurasidone hydrochloride.
Lurasidone reaches peak serum concentrations in approximately 1-3 hours.
In a food effect study, lurasidone mean Cmax and AUC increased approximately by 2-3-times and 1.5-2-times, respectively, when administered with food compared to the levels observed under fasting conditions.
Following administration of 37 mg of lurasidone, the mean approximate apparent volume of distribution was 6000 L. Lurasidone is highly bound (~99%) to serum proteins.
Lurasidone is metabolised mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation.
Lurasidone is metabolised into two active metabolites (ID-14283 and ID-14326) and two non-active metabolites (ID-20219 and ID-20220). Lurasidone and its metabolites ID-14283, ID-14326, ID-20219 and ID-20220 correspond to approximately 11.4, 4.1, 0.4, 24 and 11% respectively, of serum radioactivity respectively.
CYP3A4 is the major enzyme responsible for metabolism of the active metabolite ID-14283. Lurasidone and its active metabolite ID-14283 both contribute to the pharmacodynamic effect at the dopaminergic and serotonergic receptors.
Based on in vitro studies lurasidone is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes.
In vitro, lurasidone demonstrated no direct, or weak inhibition (direct or time-dependent) (IC50>5.9 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Based on this data, lurasidone is not expected to affect the pharmacokinetics of medicinal products that are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. For administration of medicinal products that are substrates of CYP3A4 with a narrow therapeutic range, see section 4.5.
Lurasidone is an in vitro substrate of the efflux transporters P-gp and BCRP. Lurasidone is not subject to active uptake transport by OATP1B1 or OATP1B3.
Lurasidone is an inhibitor of P-gp, BCRP and OCT1 in vitro (see section 4.5). Lurasidone is not expected to have a clinically relevant inhibitory potential on transporters OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2K or BSEP based on in vitro data.
Following administration of lurasidone, the elimination half-life was 20-40 hours. Following oral administration of a radiolabelled dose, approximately 67% dose was recovered in faeces and 19% in urine. Urine comprised mostly of a number of metabolites with minimal renal excretion of parent compound.
The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 18.5 mg to 148 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting lurasidone.
Limited data have been collected in healthy subjects ≥65 years. Of the data collected, similar exposure was obtained compared with subjects <65 years. However, an increase in exposure in elderly subjects may be expected for patients if they have impaired renal or hepatic function.
The serum concentrations of lurasidone are increased in healthy subjects with Child-Pugh Class A, B and C hepatic impairment with an increased exposure of 1.5-, 1.7- and 3-fold respectively.
The serum concentrations of lurasidone are increased in healthy subjects with mild, moderate and severe renal impairment with an increased exposure of 1.5, 1.9 and 2.0-fold respectively. Subjects with ESRD (CrCl<15 ml/min) have not been investigated.
There were no clinically relevant differences between genders in the pharmacokinetics of lurasidone in a population pharmacokinetic analysis in patients with schizophrenia.
There were no clinically relevant differences in the pharmacokinetics of lurasidone in a population pharmacokinetic analysis in patients with schizophrenia. It was noted that Asian subjects had 1.5 fold increased exposure to lurasidone compared to Caucasian subjects.
Based on in vitro studies utilising human liver enzymes, lurasidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of lurasidone.
The pharmacokinetics of lurasidone in paediatric patients was evaluated in 47 children aged 6-12 years and 234 adolescents aged 13-17 years. Lurasidone was administered as lurasidone hydrochloride at daily doses of either 20, 40, 80, 120 mg (6-17 years) or 160 mg (10-17 years only) for up to 42 days. There was no clear correlation between obtained serum exposure and age or body weight. The pharmacokinetics of lurasidone in paediatric patients aged 6–17 years was generally comparable to those observed in adults.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Major findings in repeat-dose toxicity studies of lurasidone were centrally-mediated endocrine changes resulting from serum prolactin elevations in rats, dogs and monkeys. High serum prolactin levels in long-term repeat-dose studies in female rats were associated with effects on bones, adrenal glands, and reproductive tissues. In a long-term dog repeat-dose study, high serum prolactin levels were associated with effects on male and female reproductive tissues.
In rats, lurasidone had no effect on male and female reproduction at oral doses of 150 and 0.1 mg/kg/day lurasidone hydrochloride, respectively, or on early embryonic development at an oral dose of 15 mg/kg/day lurasidone hydrochloride.
A fertility study in female rats resulted in prolonged oestrous cycle and delayed copulation at ≥1.5 mg/kg/day lurasidone hydrochloride, whilst the copulation and fertility indices, and the numbers of corpora lutea, implantations and live foetuses were decreased at 150 mg/kg/day lurasidone hydrochloride. These effects were due to the hyperprolactinemia following lurasidone treatment, affecting the oestrous cycle and copulatory behaviour as well as the maintenance of corpus luteum of the female rats, resulting in a decrease in implantation and the number of live foetuses. These prolactin-related effects are not considered to be relevant to human reproduction.
A single dose of 10 mg/kg lurasidone hydrochloride to pregnant rats resulted in fetal exposure. In a dose range finding study in pregnant rats, 150 mg/kg/day lurasidone hydrochloride caused fetal growth retardation without signs of teratogenicity. Lurasidone was not teratogenic in rats or rabbits at an exposure similar to or below the maximum recommended human dose (148 mg lurasidone).
In the definitive juvenile rat toxicity study, no increased sensitivity of juvenile animals to lurasidone-related effects on body weight, food consumption, and clinical observations were apparent, but similar effects as in adult rat were noted (delays in growth and development and hyperprolactinaemia). Hyperactivity that was evident at ≥3 mg/kg/day during the posttreatment period has also been reported for other D2 receptor antagonists. Slightly lower birth weights and body weights/body weight gains during the postnatal period were noted in the offspring of juvenile rats previously treated with ≥30 mg/kg/day. At the NOAEL of 3 mg/kg/day, the exposures of lurasidone and most metabolites were lower than that achieved at the recommended clinical dose in adolescents aged 13 years or above. Lurasidone was excreted in milk of rats during lactation.
Lurasidone was not genotoxic in a battery of tests. Mammary gland and/or pituitary gland tumours were observed in the mouse and rat carcinogenicity studies and are most likely due to the increased blood prolactin levels. These findings are common in rodents treated with antipsychotic medicinal products with dopamine D2 blocking activity and are considered to be rodent-specific.
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