5-HT2A ( Ki = 0.5 nM ); 5-HT7 receptor ( Ki = 0.5 nM ); D2 receptor ( Ki = 1 nM ); 5-HT1A receptor ( Ki = 6.4 nM )

Lurasidone (SM-13496) exhibits an antagonistic effect on dopamine D2 and 5-HT7, with IC50 values of 1.68±0.09 and 0.495±0.090 nM, respectively. Additionally, luerazidone (SM-13496) has an IC50 of 6.75±0.97 nM, making it a partial agonist of the 5-HT1A receptor. Lurasidone (SM-13496) exhibits a higher affinity for dopamine D2 and 5-HT2A receptors than other tested antipsychotics, according to in vitro receptor binding experiments. Lurasidone (SM-13496) has a KB value of 2.8±1.1 nM[1], which indicates that it opposes dopamine-stimulated [35S]GTPηS binding in a concentration-dependent manner. However, it does not increase [35S]GTPηS binding to the membrane preparations for dopamine D2 receptors on its own.

In the frontal cortex and striatum, luerazidone (SM-13496) dose-dependently raises the ratio of DOPAC/dopamine; however, it preferentially affects the frontal cortex over the striatum, particularly at higher doses. Comparable in potency to olanzapine (ED50 values 1.1 to 5.1 mg/kg), clozapine (ED50 values 9.5 to 290 mg/kg), and haloperidol (ED50 values 0.44 to 1.7 mg/kg), lurasidone (SM-13496) (ED50 values 2.3 to 5.0 mg/kg) exhibits a slightly lower potency. The ED50 values of lueradone (SM-13496) are 6.3 mg/kg, and it inhibits the conditioned avoidance response (CAR) in rats in a dose-dependent manner at 1 to 10 mg/kg. Lurasidone (SM-13496), with ED50 values of 5.6 and 3.0 mg/kg, respectively, dose-dependently inhibits p-chloroamphetamine (p-CAMP)-induced hyperthermia and tryptamine (TRY)-induced forepaw clonic seizures. Rats receive more shocks in the conflict test when given luerasidone (SM-13496) at doses ranging from 0.3 to 30 mg/kg (p<0.01), which is dose-dependent and statistically significant[1].

Methamphetamine (MAP) (1 mg/kg i.p.) is injected into each individual SD rat in a clear plastic cage one hour after the drugs or vehicle are administered. Lurasidone (SM-13496) is given 1, 2, 4, and 8 hours prior to the MAP injection in order to test the effect's persistence. Following a 10-minute MAP injection, locomotor activity is monitored for 80 minutes. The ED50 value, which inhibits MAP-induced hyperactivity by 50% of the animals tested, is determined using four or five groups of six to thirteen rats[1].

Absorption, Distribution and Excretion
Lurasidone is readily absorbed and quickly reaches maximal concentrations (Cmax) within 1-4 hours. When taken with food, there is a two-fold increase in exposure and time to maximal concentration is increased by 0.5-1.5 hours. This occurs regardless of fat or caloric content. Bioavailability = 9-19%.
Urine (~9%) and feces (~80%)
6173 L
3902 mL/min
Following administration of a single radiolabeled dose of lurasidone, approximately 80 and 9% of the dose is excreted in feces and urine, respectively.
Lurasidone is rapidly absorbed following oral administration and reaches peak serum concentrations within about 1-3 hours. Approximately 9-19% of an administered dose is absorbed orally. Steady-state concentrations of the drug are achieved within 7 days.

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Metabolism / Metabolites
Lurasidone is metabolized by CYP3A4 in which its major active metabolite is referred to as ID-14283 (25% of parent exposure). Its two minor metabolites are referred to as ID14326 and ID11614 which make up 3% and 1% of parent exposure respectively. Its two non-active metabolites are referred to as ID-20219 and ID-20220.
Lurasidone is highly bound (99.8%) to serum proteins, including albumin and alpha1-acid glycoprotein. The drug is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of the norbornane ring, and S-oxidation. Lurasidone is metabolized into 2 active metabolites (ID-14283 and ID-14326) and 2 major inactive metabolites (ID-20219 and ID-20220).

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Biological Half-Life
40 mg dose= 18 hours 120 mg - 160 mg dose = 29-37 hours

Toxicity Summary
IDENTIFICATION AND USE: Lurasidone is indicated for the treatment of patients with schizophrenia, as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression), and as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). HUMAN EXPOSURE AND TOXICITY: An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including lurasidone. Rash and pruritus have been reported frequently and angioedema has been reported rarely in patients receiving lurasidone. Adverse effects occurring in 5% or more of patients receiving lurasidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, nausea, parkinsonism, and agitation. Akathisia and somnolence appear to be dose-related adverse effects.The effect of lurasidone on labor and delivery is unknown. It is not known whether lurasidone and/or its metabolites are distributed into milk in humans. In geriatric patients (65-85 years of age) with psychosis, serum lurasidone concentrations were similar to those observed in younger adults. Geriatric patients with dementia-related psychosis treated with lurasidone are at an increased risk of death compared with those treated with placebo. Safety and effectiveness of lurasidone in pediatric and adolescent patients have not been established. ANIMAL STUDIES: Lurasidone increased the incidence of mammary gland carcinomas in females rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4-times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-times those in humans receiving the MRHD. Lurasidone is distributed into milk in rats. Estrus cycle irregularities were seen in rats orally administered lurasidone at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. The no-effect dose is 0.1 mg/kg which is approximately 0.006-times the MRHD of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose, which was reversible after a 14-day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is approximately equal to the MRHD based on body surface area. Lurasidone had no effect on fertility 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 mg/m sq body surface area). The drug did not cause mutation or chromosomal aberration when tested in vitro and in vivo. It was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg (61 times the MRHD of 160 mg/day based on mg/ sq m body surface area).

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Interactions
Lurasidone is not a substrate for CYP1A2 in vitro; therefore, smoking should not alter the pharmacokinetics of the drug.
Concomitant administration of rifampin (600 mg daily for 8 days), a strong CYP3A4 inducer, and lurasidone (single 40-mg dose) decreased peak serum lurasidone concentrations and AUCs by approximately 86 and 80%, respectively. Rifampin should not be concurrently administered with lurasidone.
Concomitant administration of lurasidone (40 mg daily at steady state) with an oral contraceptive containing ethinyl estradiol and norgestimate resulted in equivalent peak plasma concentrations and AUCs of ethinyl estradiol and norgestimate relative to oral contraceptive administration alone. Sex hormone binding globulin concentrations also were not substantially affected by concurrent administration of the drugs. Oral contraceptive dosage adjustment is not required in patients receiving lurasidone concurrently.
Concomitant administration of lurasidone (120 mg daily at steady state) with a single 5-mg dose of midazolam, a CYP3A4 substrate, increased peak plasma concentrations and AUCs of midazolam by approximately 21 and 44%, respectively. Midazolam dosage adjustment is not required in patients receiving lurasidone concurrently.
For more Interactions (Complete) data for Lurasidone (11 total), please visit the HSDB record page.

[1]. Pharmacological profile of lurasidone, a novel antipsychotic agent with potent 5-hydroxytryptamine 7 (5-HT7) and 5-HT1A receptor activity. J Pharmacol Exp Ther. 2010 Jul;334(1):171-81.

[2]. Development of a validated high-performance liquid chromatographic method for the determination of Lurasidone in pharmaceuticals. Marmara Pharm J. 2017;21 (4): 931-937.

Lurasidone is an N-arylpiperazine that is (3aR,4S,7R,7aS)-2-{[(1R,2R)-2-(piperazin-1-ylmethyl)cyclohexyl]methyl}hexahydro-1H-4,7-methanoisoindole-1,3(2H)-dione in which position N4 of the piperazine ring is substituted by a 1,2-benzothiazol-3-yl group. Lurasidone is used (generally as the hydrochloride salt) as an atypical antipsychotic for the treatment of schizophrenia. It has a role as an adrenergic antagonist, a dopaminergic antagonist, a serotonergic antagonist and a second generation antipsychotic. It is a 1,2-benzisothiazole, a N-arylpiperazine, a bridged compound and a dicarboximide. It is functionally related to a maleimide. It is a conjugate base of a lurasidone(1+).
Lurasidone is an atypical antipsychotic developed by Dainippon Sumitomo Pharma. It was approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia on October 29, 2010 and is currently pending approval for the treatment of bipolar disorder in the United States.
Lurasidone is an Atypical Antipsychotic.
Lurasidone is a second generation (atypical) antipsychotic agent that is used in the treatment of schizophrenia and bipolar depression. Lurasidone is associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent acute liver injury.
A thiazole derivative and atypical ANTIPSYCHOTIC AGENT that functions as a DOPAMINE D2 RECEPTOR ANTAGONIST; SEROTONIN 5-HT2 RECEPTOR ANTAGONIST, serotonin 5-HT7 receptor antagonist, and antagonist of the adrenergic α2A and α2C receptors, as well as a partial SEROTONIN 5-HT1A RECEPTOR AGONIST. It is used in the treatment of SCHIZOPHRENIA and BIPOLAR DISORDER.
See also: Lurasidone Hydrochloride (has salt form).

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Drug Indication
Lurasidone is indicated for the treatment of schizophrenia in patients ≥13 years old. It is also indicated as a monotherapy for the treatment of bipolar depression in patients ≥10 years old, or in combination with lithium or valproate for the treatment of bipolar depression in adults.
Treatment of schizophrenia in adults aged 18 years and over.

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Mechanism of Action
Lurasidone is an atypical antipsychotic that is a D2 and 5-HT2A (mixed serotonin and dopamine activity) to improve cognition. It is thought that antagonism of serotonin receptors can improve negative symptoms of psychoses and reduce the extrapyramidal side effects that are often associated with typical antipsychotics.
Lurasidone is a benzisothiazol-derivative antipsychotic agent and has been referred to as an atypical or second-generation antipsychotic agent. Lurasidone has also been described as an azapirone-derivative. Although the exact mechanism of action of lurasidone and other antipsychotic agents in schizophrenia is unknown, it has been suggested that the efficacy of lurasidone is mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2A]) receptors. Lurasidone is an antagonist that exhibits high affinity for D2, 5-HT2A, and 5-HT7 receptors and moderate affinity for a2C-adrenergic receptors in vitro. The drug acts as a partial agonist at 5-HT1A receptors and is an antagonist at alpha2A-adrenergic receptors in vitro. Lurasidone exhibits weak affinity for alpha1-adrenergic receptors and little or no affinity for histamine (H1) receptors and muscarinic (M1) receptors.

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Therapeutic Uses
Latuda is indicated for the treatment of patients with schizophrenia. /Included in US product label/
Latuda is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). /Included in US product label/
Latuda is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). /Included in US product label/
The efficacy of Latuda in the treatment of mania associated with bipolar disorder has not been established.
The effectiveness of Latuda for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use Latuda for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient

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Drug Warnings
/BOXED WARNING/ WARNINGS: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS AND BEHAVIORS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Latuda is not approved for use in patients with dementia-related psychosis. Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber.
Contraindications: Known hypersensitivity to lurasidone hydrochloride or any components in the formulation. Angioedema has been reported. Concurrent administration of strong cytochrome P-450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., ketoconazole) or strong CYP3A4 inducers (e.g., rifampin).
Geriatric patients with dementia-related psychosis treated with antipsychotic drugs appear to be at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.
For more Drug Warnings (Complete) data for Lurasidone (27 total), please visit the HSDB record page.

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Pharmacodynamics
Lurasidone is a benzothiazol derivative that is an antagonist and binds with high affinity to Dopamine-2 (D2) (Ki = 0.994 nM), 5-HT2A (Ki = 0.47 nM) receptors, and 5-HT7 receptors (Ki = 0.495 nM). It also binds with moderate affinity to alpha-2C adrenergic receptors (Ki = 10.8 nM) and is a partial agonist at 5-HT1A receptors (Ki = 6.38 nM). Its actions on histaminergic and muscarinic receptors are negligible.

C28H36N4O2S

492.682

492.255

C, 68.26; H, 7.37; N, 11.37; O, 6.49; S, 6.51

367514-87-2

Lurasidone Hydrochloride; 367514-88-3; Lurasidone metabolite 14326 hydrochloride; Lurasidone-d8; 1132654-54-6; Lurasidone-d8 hydrochloride; Lurasidone metabolite 14326; 186204-33-1

213046

White to off-white solid powder

1.3±0.1 g/cm3

623.4±55.0 °C at 760 mmHg

330.8±31.5 °C

0.0±1.8 mmHg at 25°C

1.637

4.52

0

6

5

35

804

6

O=C([C@H]1[C@H]2C[C@H](CC2)[C@@H]31)N(C[C@H](CCCC4)[C@@H]4CN5CCN(CC5)C6=NSC7=CC=CC=C67)C3=O

PQXKDMSYBGKCJA-CVTJIBDQSA-N

InChI=1S/C28H36N4O2S/c33-27-24-18-9-10-19(15-18)25(24)28(34)32(27)17-21-6-2-1-5-20(21)16-30-11-13-31(14-12-30)26-22-7-3-4-8-23(22)35-29-26/h3-4,7-8,18-21,24-25H,1-2,5-6,9-17H2/t18-,19+,20-,21-,24+,25-/m0/s1

(1S,2R,6S,7R)-4-[[(1R,2R)-2-[[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]methyl]cyclohexyl]methyl]-4-azatricyclo[5.2.1.02,6]decane-3,5-dione

trade name Latuda; SM 13496; SM-13496; SM13496

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 7~20.83 mg/mL (14.2~42.3 mM)
Ethanol: ~3.3 mg/mL (~6.8 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.22 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)