Latuda
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Latuda - Scientific Information

Manufacture: Sunovion Pharmaceuticals Inc.
Country: Canada
Condition: Bipolar Disorder, Schizophrenia
Class: Atypical antipsychotics
Form: Tablets
Ingredients: lurasidone hydrochloride, carnauba wax, croscarmellose sodium, hypromellose, magnesium stearate, mannitol, Opadry (hypromellose, polyethylene glycol, and titanium dioxide), pregelatinized starch; 80 mg tablet also contains: FDandC Blue No.2 Aluminum Lake and yellow ferric oxide.

Pharmaceutical information

Drug Substance

Proper name: lurasidone hydrochloride
Chemical name: (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride
Molecular formula and molecular mass: C28H36N4O2S·HCl
M.W: 529.14

Structural formula:


Physicochemical properties: White to off-white powder
Very slightly soluble in water
Practically insoluble or insoluble in 0.1 N HCl
Slightly soluble in ethanol
Sparingly soluble in methanol
Practically insoluble or insoluble in toluene
Very slightly soluble in acetone

Clinical trials

Schizophrenia

Study Demographics and Trial Design

The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active control arm (olanzapine or quetiapine XR) was included in two studies to assess assay sensitivity; the studies were not designed to compare LATUDA to the active comparators. In four of the five short-term studies, the study drug was administered once daily in the morning with a meal or within 30 minutes after eating, although evening dosing was permitted with Medical Monitor approval. In the fifth study, comparing LATUDA 80 mg and 160 mg doses and quetiapine XR 600 mg dose to placebo, the study drug was administered once daily in the evening with a meal or within 30 minutes after eating and efficacy and safety assessments were performed the next morning.

In two additional short-term (6-week), placebo-controlled studies, neither LATUDA (20 mg, 40 mg, or 80 mg) nor the active comparators (haloperidol 10 mg/day or risperidone 4 mg/day) showed superiority to placebo in the primary efficacy outcome, and thus were considered failed studies.

Several instruments were used for assessing psychiatric signs and symptoms in these studies:

  1. Positive and Negative Syndrome Scale (PANSS) is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
  2. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative, and other symptoms of schizophrenia. BPRSd scores may range from 18 to 126.
  3. The Clinical Global Impression severity scale (CGI-S) is a validated clinician-rated scale that measures the subject’s current illness state on a 1 to 7-point scale.

The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups.

Study Results

The results of the positive studies follow:

  1. In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score and the CGI-S score.
  2. In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score and the CGI-S score.
  3. In a 6-week, placebo and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine) to assess study assay sensitivity, both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score and the CGI-S score.
  4. In a 6-week, placebo-controlled trial (N=489) involving three fixed doses of LATUDA (40, 80, or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score and the CGI-S score.
  5. In a 6-week, placebo, and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine XR) to assess study assay sensitivity, both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score and the CGI-S score.

Bipolar Depression

Study Demographics and Trial Design

Monotherapy

The efficacy of LATUDA, as monotherapy, was established in a 6-week, randomized, double- blind, placebo-controlled study of adult patients (mean age of 41.5 years, range 18-74) who met DSM-IV-TR criteria for depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N=485). Patients were randomized to flexibly dosed LATUDA 20-60 mg/day, LATUDA 80-120 mg/day or placebo. Primary and key secondary efficacy assessments were conducted at baseline and Weeks 1 through 6.

The primary rating instrument used to assess depressive symptoms in this study was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with total scores ranging from 0 (no depressive features) to 60 (maximum score). The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the Clinical Global Impression-Bipolar-Severity of Illness scale (CGI-BP-S), a clinician-rated scale that measures the subject’s current illness state on a 7-point scale, where a higher score is associated with greater illness severity.

Adjunctive Therapy

The efficacy of LATUDA, as an adjunctive therapy to lithium or valproate, was evaluated in two (N=340 and 342) 6-week, randomized, double-blind, placebo-controlled studies of adult patients (mean age of 42.6 years, range 18-74) who met DSM-IV-TR criteria for depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features. Patients who remained symptomatic during treatment with lithium or valproate were randomized to flexibly dosed LATUDA 20-120 mg/day or placebo. Primary and key secondary efficacy assessments were conducted at baseline and Weeks 1 through 6.

The primary rating instrument used to assess depressive symptoms in this study was the MADRS. The primary endpoint was the change from baseline in MADRS score at Week 6. The key secondary instrument was the CGI-BP-S scale.

Study Results

Monotherapy

LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores at Week 6. The high dose group (80-120 mg) did not provide improved efficacy on average compared to the low dose group (20-60 mg). Significant treatment differences in MADRS and CGI-BP-S were observed at Week 2 for LATUDA 20-60 mg which were sustained for the remainder of the study. The proportion of patients with ≥ 50% improvement in MADRS was significantly greater (p<0.001) in both LATUDA flexible-dose groups (53% LATUDA 20-60 mg; 51% LATUDA 80-120 mg) vs. placebo (30%). Both LATUDA dose groups were associated with significantly greater improvement than placebo on seven of the 10 MADRS items (p<0.05).The secondary endpoints supported the superiority of LATUDA over placebo.

Adjunctive Therapy

In one study, LATUDA was superior to placebo in reduction of MADRS and CGI-BP-S scores as an adjunctive therapy to lithium or valproate at Week 6. Significant treatment differences were observed in the LATUDA + lithium or valproate dose group at Week 3 in MADRS and at Week 2 in the CGI-BP-S which were sustained for the remainder of the study. The proportion of patients with ≥ 50% improvement in MADRS was significantly greater (p=0.008) in the LATUDA + lithium or valproate dose group (57%) vs. placebo (42%). LATUDA was associated with significantly greater improvement than placebo on six of the 10 MADRS items (p<0.05) The secondary endpoints supported the superiority of LATUDA over placebo.

In a second study, a statistically significant difference was not demonstrated between LATUDA and placebo for the primary endpoint (MADRS) at Week 6.

Detailed pharmacology

Nonclinical Pharmacodynamics

Receptor Binding

in vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D2 receptors (Ki = 0.994 nM), D2L receptors (Ki = 0.329 and 0.994 nM), and the 5- hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki = 0.47 nM) and 5-HT7 (Ki = 0.495 nM), is an antagonist with moderate affinity at human α2C adrenergic receptors (Ki = 10.8 nM), is a partial agonist at serotonin 5-HT1A (Ki = 6.38 nM) receptors, and is an antagonist at α2A adrenergic receptors (Ki = 40.7 nM). Lurasidone exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 > 1,000 nM).

Schizophrenia

Pharmacological studies have shown that lurasidone was effective in various animal models of schizophrenia induced by methamphetamine or tryptamine, and confirmed its potent dopamine D2-blocking and serotonin 5-HT2-blocking actions.

Bipolar Depression

Pharmacological studies have shown that lurasidone was effective in some animal models of depression.

Effects on the Central Nervous System

Lurasidone, when intravenously administered at high doses, slowed spontaneous electroencephalogram (EEG) in rabbits, and inhibited emetic response in apomorphine-treated dogs following oral administration, but exerted no other potent effects on the CNS (anti- acetylcholine action, anti-hypoxic action, effects on cerebral blood flow, convulsion facilitating action, and anti-adrenergic action).

Lurasidone demonstrated mild anti-histamine and anti-noradrenaline effects but not anti- acetylcholine effect in in vitro studies.

Effects on Cardiovascular System

In addition to the animal studies of antipsychotic efficacy and mechanism of action, a safety pharmacological evaluation of lurasidone was conducted to obtain a more extensive characterization of its actions on various organ systems in vitro and in vivo. Potential cardiovascular effects were assessed in in vitro and in vivo safety pharmacology and toxicology studies. In HEK293 cells stably expressing the hERG gene, lurasidone and its metabolites, ID- 14326 and ID-14283, caused concentration-dependent suppression of hERG currents with IC50 values of 57 ng/mL, 357 ng/mL, and 434 ng/mL, respectively. There were no effects on action potential duration (APD) in guinea pig papillary muscle and on inotropic/chronotropic action in guinea pig atrium.

Conscious telemetered female dogs (N=4/treatment) received single oral doses of vehicle, lurasidone 100 mg/kg, lurasidone 300 mg/kg, or sotalol according to Latin square crossover design. Lurasidone 100 mg/kg and 300 mg/kg caused statistically significant increases in heart rate. Lurasidone 300 mg/kg also caused a statistically significant increase in the QTc interval. Cmax values were reported to be 1.9 μg/mL for lurasidone 100 mg/kg and 2.8 μg/mL for lurasidone 300 mg/kg. In a 39-week, repeated oral doses toxicology study in dogs, lurasidone showed QTc prolongation in 1 out of 4 male dogs in the 100 mg/kg group and 2 out of 4 male dogs in the 200 mg/kg group. QT prolongation effect of lurasidone in dogs arises at 12- to 20- fold higher plasma levels than the plasma Cmax associated with the maximum dose evaluated in clinical trials.

Nonclinical Pharmacokinetics

The pharmacokinetic parameters (absorption, distribution, metabolism, and excretion) of lurasidone have been studied in mice, rats, dogs, rabbits, and monkeys.

Lurasidone is rapidly absorbed with peak systemic exposure occurring within 5.3 hours of administration. The absolute bioavailability is low, <12%, in all species examined. Administration of lurasidone with food increases the extent of absorption two- to three-fold. Clearance ranged from 17 to 61 mL/min/kg and volume of distribution ranged from 2.4 to 20 L/kg. Terminal elimination half-life is also variable, ranging from 1.6 to 27 hours.

Lurasidone binds extensively (>99% bound) to serum proteins including human serum albumin and α-glycoprotein. Distribution into red blood cells is moderate with blood:plasma ratios ranging from 0.57 – 0.80. Lurasidone distributes into most tissues including the brain and into the fetus.

Lurasidone is extensively metabolized with oxidative N-dealkylation, hydroxylation of the norbornane ring or cyclohexane ring, S-oxidation, reductive cleavage of the isothiazole ring followed by S-methylation, and a combination of two or more of these pathways. Although many metabolites were found in human serum, all primary metabolites were detected in one or more of the nonclinical animal species; therefore, no human specific metabolites have been identified.

The primary metabolizing Cytochrome P450 (CYP) isozyme in humans is CYP3A4. Specific metabolizing isozymes in nonclinical species have not been identified. In vitro studies conducted with human tissue preparations suggest that at clinically relevant concentrations lurasidone does not inhibit or induce CYP enzyme activity. The potential for protein-based clinical drug-drug interactions appears to be minimal as no displacement of lurasidone or co- incubated drugs from serum proteins is observed in vitro. Although lurasidone is not a substrate of P-glycoprotein (P-gp), lurasidone demonstrates an inhibitory effect on P-gp transport activity.

Following administration of [14C]lurasidone, the majority of the radioactivity was excreted in feces as parent compound. Approximately 12-48% of the orally administered dose was absorbed. Unchanged parent compound is detected only at trace levels in bile and urine, indicating that the absorbed material is subject to extensive metabolism. Lurasidone is excreted into rat milk primarily as unchanged drug at concentrations that are greater than those in serum.

Toxicology

Single-Dose Toxicity

In single-dose studies performed in rats and monkeys, there were no deaths at the highest dose levels of 2000 mg/kg in either species. The target organ for acute toxicity is the CNS. Clinical signs in rats consisted of decreased spontaneous activity, ptosis, and decreased body weight and/or body weight gain at ≥1000 mg/kg and ataxic gait at 2000 mg/kg. Treatment-related clinical signs in monkeys included decrease of spontaneous activity in all treated groups (10 to 2000 mg/kg), tremor, and decrease of spontaneous activity accompanied by extrapyramidal symptoms such as persistent abnormal posture and slow movement at 50 mg/kg or higher, closed eyelids at 250 mg/kg, and miosis, closed eyelids, and vomiting at 2000 mg/kg. Food consumption was reduced at 250 mg/kg or higher.

Serum concentrations of lurasidone and prolactin were evaluated after a single oral dose of lurasidone at levels up to 1000 mg/kg in rats. The concentrations of serum prolactin at one (peak level) and two hours after administration, at almost all doses of 10 mg/kg and above, were significantly higher (up to 44-fold control levels) or tended to be higher than the control values, with little or no dose dependency. The increases in peak serum levels and total exposure of lurasidone were dose-dependent up to 500 mg/kg in male rats and up to 1000 mg/kg in female rats.

Repeat-Dose Toxicity

Repeat-dose toxicity studies from 2 to 52 weeks in duration were performed in mice, rats, dogs, and monkeys.

Toxic responses to orally administered lurasidone were rapid in onset. The main target organs of toxicity are the CNS and the endocrine system. Like other antipsychotic drugs that bind to dopamine D2 receptors, lurasidone has been shown to elevate serum prolactin levels in mice, rats, dogs, and monkeys.

Clinical signs evident after repeated doses included decreased spontaneous activity and extrapyramidal effects in rats, dogs, and monkeys. Prolactin-related effects were similar in rodents and dogs regarding histopathologic changes in the mammary glands. Mild signs of mammary development (1 female) and lactogenesis (1 female) were observed in monkeys. Prostatic changes were observed only in dogs, vaginal changes were observed only in rodents, whereas pituitary changes were seen in rodents and monkeys. Prolactin-related fatty infiltration into bone marrow and reduced bone density were seen in rats, but were not observed in mice. Similar changes were seen in a few high-dose dogs that were suffering from emaciation, but which were considered secondary effects of increased corticosteroid secretion in response to the stress of their condition.

Cardiac effects were not determined in the mouse and rat, and were not seen in the monkey at any dose level, but QT prolongation and/or PVC were observed in the dog toxicology studies. Signs of anemia were observed in the 4-week dog study but not in the 39-week study. Except for some of the effects on bone, these clinical signs resolved upon withdrawal of treatment and are considered to represent exaggerated pharmacology of the drug, relating mostly to hyperprolactinemia, or CNS and cardiovascular effects, all commonly seen with D2 receptor antagonist antipsychotic agents. The dosing regimens used in the various repeated-dose studies consisted of once-daily administration by oral gavage in mice, rats, and dogs, and by intranasal gastric gavage in monkeys. In each case the vehicle was 0.5% aqueous methylcellulose.

Mouse Study

All dose levels in the 3-month mouse study (25 to 500 mg/kg/day) produced adverse effects, consisting mainly of decreased spontaneous activity, and effects on female sex organs that were attributed to increased prolactin levels. The NOAEL is less than 25 mg/kg/day for repeated dosing in this species, and the corresponding safety margins for these effects, relative to man at the MRHD of 160 mg/day, are less than 0.38 (males) or less than 0.64 (females) from comparisons based upon peak serum exposure levels of lurasidone, and less than 0.37 (males) or less than 0.60 (females) based upon total serum exposure levels of lurasidone.

Rat Studies

The 90-day NOAEL in male and female rats is 0.3 and 0.1 mg/kg/day, respectively, based upon the combined results of the two 3-month studies performed in Sprague-Dawley rats. The safety margins, based upon peak serum levels relative to man at the MRHD, are 0.005 and 0.001, respectively. Based upon the results of the 6-month study, the NOAEL in rats of either sex is 0.03 mg/kg/day. Dosage administration at levels at or above 1 mg/kg/day for 6 months produced changes in male mammary glands and elevated hemoglobin concentrations, along with elevated prolactin levels. Adverse effects seen in females at these same dose levels included effects on female sex organs and increased incidence of fatty infiltration into the femur marrow, thickened zona glomerulosa of adrenal, and decreased total bone mineral density of femur. The resultant safety margin, based upon peak serum levels relative to man at the MRHD, are 0.0006 and 0.0003, for males and females, respectively.

Dog Studies

All dose levels in both the 4-week and 39-week repeated-dose studies in the Beagle dog produced adverse effects attributed to increased prolactin levels. Both studies utilized 30 mg/kg/day as the lowest dose. In the 4-week study, a 30 mg/kg/day dose produced effects in the thymus and mammary glands. The same dose level in the 39-week study also produced effects on the thymus in males, but more severe mammary effects as well as changes in the uterus and ovary in females and in the prostate of males. All dose levels produced CNS effects (decreased spontaneous activity, tremors, miosis, and somnolence). Thymic atrophy or involution were seen in both dog studies, and increased total cholesterol and phospholipids as well as increased cytoplasmic eosinophilic granule epithelium in urinary bladder were observed at or above 30 mg/kg/day in the 39-week study. The NOAEL is less than 30 mg/kg/day for repeated dosing of lurasidone in the dog, and the corresponding safety margins for these effects, relative to man at the MRHD of 160 mg/day, are less than 3.4 (4 weeks) or less than 4.9 (39 weeks) based upon peak serum levels of lurasidone and less than 3.1 (4 weeks) or less than 11/9.2 (M/F, 39 weeks) based upon total exposure levels.

Monkey Studies

There were no significant prolactin-related adverse effects in the 3-month and 1-year repeated- dose studies in Cynomolgus monkeys. The observations of decreased spontaneous activity, movement disorder, and abnormal posture were considered CNS effects and not directly related to prolactin levels. The only minor finding that was possibly related to prolactin was the presence of enlarged pale staining cells in the pituitary, which were observed upon histopathologic examination in both sexes at 50 mg/kg/day in the 1-year study. Mean serum prolactin concentrations at 4 hours after dosing were increased in a dose-related fashion in all treated groups in both studies.

If one considers the elevation of prolactin levels as a non-adverse effect, the CNS effects observed at 10 and 2 mg/kg/day in the 3-month and 1-year monkey studies, respectively, put the NOAEL for monkeys near 2 mg/kg/day. Safety margins (1-year study) at the MRHD were 0.01 to 0.03 (based on Cmax) and 0.02 to 0.03 (based on AUC).

Reproductive and Developmental Toxicity

Lurasidone was administered orally to female rats at doses of 0.1, 1.5, 15, or 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. Estrus cycle irregularities were seen at 1.5 mg/kg and above; the no-effect dose of 0.1 mg/kg is approximately 0.006 times the maximum recommended human dose (MRHD) of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose and this was shown to be reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is 0.9 times the MRHD based on body surface area.

Fertility was not affected in male rats treated orally with lurasidone for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (9 times the MRHD based on body surface area).

No teratogenic effects were seen in studies in which pregnant rats and rabbits were given lurasidone during the period of organogenesis at doses up to 25 and 50 mg/kg/day, respectively. These doses are 1.5 and 6 times, in rats and rabbits, respectively, the MRHD based on body surface area.

No adverse developmental effects were seen in a study in which pregnant rats were given lurasidone during the period of organogenesis and continuing through weaning at doses up to 10 mg/kg/day; this dose is approximately half of the MRHD based on body surface area.

Carcinogenicity

Lifetime carcinogenicity studies were conducted in ICR mice and Sprague-Dawley rats. Lurasidone was administered orally at doses of 30, 100, 300, or 650 (the high dose was reduced from 1200 in males) mg/kg/day to ICR mice and 3, 12, or 36 (high dose reduced from 50) mg/kg/day to Sprague-Dawley rats.

In the mouse study, there were increased incidences of malignant mammary gland tumors and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 7 - 13 times those in humans receiving the MRHD.

In rats, an increased incidence of mammary gland carcinomas was seen in females at the two higher doses; the no-effect dose of 3 mg/kg produced plasma levels (AUC) 0.4 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to highest dose tested, which produced plasma levels (AUC) 6 times those in humans receiving the MRHD.

Mutagenesis

The potential for the genotoxicity of lurasidone has been adequately studied in varied test systems including in vitro assays in bacterial and mammalian cell systems (with and without metabolic activation) and in an in vivo micronucleus assay in mice. Lurasidone was shown not to be mutagenic or clastogenic under the conditions of these well-controlled assays.

Drug Dependence

The drug dependence studies in rats and monkeys did not indicate potential for lurasidone to induce psychic and physical dependence. Lurasidone was not self-administered by monkeys trained to self-administer barbiturate, did not suppress barbiturate withdrawal signs, and did not produce withdrawal signs after discontinuation of repeated dosing.

Antigenicity

Lurasidone caused delayed-type allergic reactions under strong sensitizing conditions in which it was subcutaneously administered at a dose 3 times the proposed clinical dose of 160 mg/day, along with Freund’s complete adjuvant. However, as lurasidone did not show antigenicity in active systemic anaphylactic reaction assays, passive cutaneous anaphylactic reaction assays, or gel precipitation reaction nor on intradermal tests when orally administered, it is unlikely that lurasidone will show antigenicity when orally administered to humans.

Phototoxicity

Oral administration of lurasidone to rats prior to irradiation with ultraviolet A (UVA) radiation at a dose of 10 J/cm2 produced no remarkable skin reaction or increase in ear thickness. It was concluded that lurasidone had no phototoxic effect on the skin under the conditions of the present study and is unlikely to show phototoxicity when orally administered to humans.