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.

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In vitro activity: Lurasidone inhibits the binding of [35S]GTPγS at the human dopamine D2L receptor in a concentration-dependent manner with a KB value of 2.8 nM. Lurasidone, at a KB value of 2.6 nM, counteracts the accumulation of cAMP induced by 5-HT in CHO/h5-HT7 cells. Lurasidone has a maximum effect of 33% and partially stimulates [35S]GTPγS binding to the human 5-HT1A receptor membrane preparation. In the rat frontal cortex and striatum, lorazidone dose-dependently raises the ratio of DOPAC/dopamine.

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To investigate whether iloperidone and Lurasidone affect the activity of CYP enzymes, the probe reaction assays were conducted with varied concentration of the neuroleptics. The Dixon`s plots of the metabolism of CYP-specific substrates, carried out in human liver microsomes and supersomes CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4, in the absence or presence of the tested neuroleptics, showed that the examined neuroleptics exerted inhibitory effects on different CYP enzymes. However, their potency to inhibit specific CYP enzymes was diverse. Iloperidone exerted a strong inhibitory effect on the activity of CYP3A4 (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 (Ki = 2.9 and 10 µM in liver microsomes and supersomes, respectively). Moreover, iloperidone attenuated the activity of CYP2C19 (Ki = 6.5 and 32 µM in liver microsomes and supersomes, respectively) and CYP1A2 (Ki = 45 and 31 µM in liver microsomes and supersomes, respectively). Iloperidone did not affect the activity of CYP2C9. In comparison, Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in liver microsomes and supersomes, respectively), CYP2C9 (Ki = 18 and 3.5 µM in liver microsomes and supersomes, respectively), CYP2C19 (Ki = 18 and 18.4 µM in liver microsomes and supersomes, respectively) and CYP3A4 (Ki = 29.4 and 9.1 µM in liver microsomes and supersomes, respectively). Lurasidone weakly diminished the activity of CYP2D6 (Ki = 37.5 and 85 µM in liver microsomes and supersomes, respectively).[3]
Lineweaver–Burk’s plots referring to the kinetics of enzyme inhibition suggested that in both human liver microsomes and supersomes iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism, CYP2D6 via a competitive mechanism, CYP1A2 and CYP2C19 via a mixed mechanism (inserts in Figs. 1, 3, 4, 5). On the other hand, Lurasidone inhibited the activity of CYP1A2, CYP2C9 and CYP2C19 via a mixed mechanism, CYP3A4 and CYP2D6 via a competitive mechanism (inserts in Figs. 1, 2, 3, 4, 5. The Ki values and mechanisms of inhibition of major human CYP enzyme activities by iloperidone and Lurasidone are summarized in Table 1 [1].

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].

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Lurasidone's inhibitory effects on MAP-induced hyperactivity last longer than eight hours. At one, two, four, and eight hours following treatment, the corresponding ED50 values of the action are 2.3 mg/kg, 0.87 mg/kg, 1.6 mg/kg, and 5.0 mg/kg. In rats with an ED50 of 6.3 mg/kg, lurasidone (1 mg/kg–10 mg/kg) dose-dependently inhibits the conditioned avoidance response. Rats treated with lurasidone (ED50 = 5.6 mg/kg) or 3.0 mg/kg show dose-dependent inhibition of TRY-induced forepaw clonic seizure and p-CAMP-induced hyperthermia, respectively. In the Vogels conflict test, rats given a MED of 10 mg/kg receive a dose-dependent and statistically significant increase in the number of shocks (0.3 mg/kg–30 mg/kg). In rats with olfactory bulbectomy models, luerasdone (3 mg/kg, 2 weeks) dramatically reduces hyperactive behavior. The duration of the loss of righting reflexes in mice induced by hexobarbital (anesthesia) is slightly prolonged by luridodone (700 mg/kg–1000 mg/kg) in a dose-dependent manner. The MK-801-induced impairment of rats' passive-avoidance response is significantly and dose-dependently reversed by luerisdone (30 mg/kg, p.o.). In rats, MK-801-induced learning impairment in the Morris water maze test is potently reversed by luerasdone (3 mg/kg p.o.). By using the radial-arm maze test, lurasidone (3 mg/kg p.o.) potently reverses the reference memory impairment caused by MK-801 and moderately, but not significantly, attenuates the working memory impairment caused by MK-801. In the rat prefrontal cortex and, to a lesser extent, the hippocampus, lorisidone (10 mg/kg) treatment raises total BDNF mRNA levels. Without affecting the protein levels of neurotrophin (precursor and mature forms) in hippocampal extracts, luerisdone (10 mg/kg) dramatically raises the levels of mature BDNF protein in the rat prefrontal cortex.

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Lurasidone (SM-13496) is a novel atypical antipsychotic with high affinities to dopamine D2, serotonin 5-HT7, 5-HT2A, 5-HT1A receptors and α2C adrenoceptor. In this study, the effects of lurasidone on the rat passive-avoidance response and its impairment by the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (dizocilpine) were evaluated and compared with those of other antipsychotics. The passive-avoidance response was examined by measuring the step-through latency, 1 day after the animals received foot-shock training. When given before the training session, lurasidone did not affect the passive-avoidance response at any dose tested (1–30 mg/kg, p.o.). All the other atypical antipsychotics examined (i.e., risperidone, olanzapine, quetiapine, clozapine and aripiprazole), however, significantly reduced the step-through latency at relatively high doses. A pre-training administration of lurasidone significantly and dose-dependently reversed the MK-801-induced impairment of the passive-avoidance response. At doses lower than those that affected the passive-avoidance response, risperidone, quetiapine, and clozapine partially reduced the MK-801-induced impairment, whereas haloperidol, olanzapine, and aripiprazole were inactive. In addition, the post-training administration of lurasidone was as effective in countering the MK-801 effect as the pre-training administration, suggesting that lurasidone worked, at least in part, by restoring the memory consolidation process disrupted by MK-801. These results suggest that lurasidone is superior to other antipsychotics in improving the MK-801-induced memory impairment and may be clinically useful for treating cognitive impairments in schizophrenia. [2]

In Vitro Receptor Binding Profile [1]
As shown in Table 2, in vitro receptor binding experiments revealed that Lurasidone demonstrates affinity for dopamine D2 and 5-HT2A receptors higher than other tested antipsychotics. In contrast to other agents, lurasidone also displayed high affinity for 5-HT7, 5-HT1A, and noradrenaline α2C receptors (Ki values, 0.495, 6.75, and 10.8 nM, respectively). Lurasidone had lower affinity for noradrenergic α1 and α2A receptors (Ki values 47.9 and 40.7 nM, respectively) and only negligible affinities...

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Determination of CYP enzyme activities [3]
To study the inhibitory effects of iloperidone and Lurasidone on the activity of various CYP isoforms, pooled human liver microsomes and microsomes from baculovirus-infected insect cells expressing human CYPs (supersomes) were used. The following probe reactions were applied, according to the methods previously described: caffeine 3-N-demethylation for CYP1A2 (caffeine 200, 400 and 800 µM), diclofenac 4′-hydroxylation for CYP2C9 (diclofenac 5, 10, 25 µM), perazine N-demethylation for CYP2C19 (perazine 50, 100, 200 µM), bufuralol 1′-hydroxylation for CYP2D6 (bufuralol 10, 25, 50 µM), and testosterone 6β-hydroxylation for CYP3A4 (50, 100 and 200 µM). Incubation systems for CYP2C9, 2C19 and 3A4 contained: 50 mM TRIS/KCL buffer (pH = 7.4), NADPH generating system (1 mM NADP, 5 mM glucose 6-phosphate, 1.7 U/ml glucose 6-phosphate dehydrogenase, 1 mM EDTA and 3 mM MgCl2). Incubation mixture for CYP1A2 included: 0.15 M phosphate buffer (pH = 7.4) and 1 mM NADPH, and for CYP2D6: 0.1 M TRIS/KCL buffer (pH = 7.4), NADPH generating system (1.3 mM NADP, 3.3 mM glucose 6-phosphate, 1 U/ml glucose 6-phosphate dehydrogenase and 3.3 mM MgCl2). The appropriate concentrations of human liver microsomes (0.5 mg/ml for each reaction) or supersomes (50 pmol CYP/ml), various concentrations of a probe substrate in the absence or presence of neuroleptic (concentrations: 0.1, 0.5, 1, 5, 10 µM) were added, The final volume of the reaction mixture was 0.5 ml. The incubation time for supersomes was 30 min (for each reaction) and for liver microsomes: 30 min (diclofenac 4′-hydroxylation and bufuralol 1′-hydroxylation), 20 min (perazine N-demethylation and testosterone 6β-hydroxylation) or 50 min (caffeine 3-N-demethylation). After the reactions had been stopped, the concentrations of specific substrates and their metabolites formed in liver microsomes or supersomes were assessed by the HPLC method with UV detection (or fluorimetric detection for CYP2D6), as described previously.

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Determination of kinetic parameters, Ki values and the mechanism of inhibition [3]
Kinetic parameters (Km, Vmax, Ki) describing the course of CYP-specific reactions in liver microsomes or supersomes were obtained using the Michaelis–Menten approach and a non-linear regression analysis. The inhibitory effects of iloperidone and Lurasidone on CYP enzymes are presented graphically as Dixon’s plots (1/V against I) indicating Ki values, and Lineweaver–Burk’s plots (1/V against 1/S) showing the mechanism of inhibition (competitive inhibition increases the Km value, not affecting the Vmax value; non-competitive inhibition decreases the Vmax value, not affecting the Km value; mixed inhibition entails respective changes in both the Km and Vmax values).

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].

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Lurasidone hydrochloride, haloperidol, olanzapine, aripiprazole, risperidone, quetiapine hemifumarate, and clozapine were prepared. The previously reported anti-dopamine ED50 values (mg/kg, p.o.) were used to adjust the test dosage of each antipsychotic drug to a level expected to block dopamine D2 receptors in vivo, i.e., 1–30 mg/kg p.o. for Lurasidone and quetiapine; 0.3 and 1 mg/kg p.o. for haloperidol; 0.3–3 mg/kg for risperidone; 0.3–10 mg/kg for olanzapine and aripiprazole; and 0.3–30 mg/kg p.o. for clozapine (Hirose et al., 2004, Migler et al., 1993, Moore et al., 1992, Sakamoto et al., 1997). All the antipsychotic drugs were dissolved or suspended in 0.5% methylcellulose (MC) as the vehicle, and orally administered at a volume of 5 ml/kg. In the cases in which Lurasidone was injected intravenously, the drug was dissolved in 25% polyethylene glycol, and injected at 1 ml/kg into the tail vein. In this case, anti-dopaminergic doses of 0.1 and 0.3 mg/kg, which effectively antagonize methamphetamine-induced hyperactivity in rats (data not shown), were used. (+)-MK-801 hydrogen maleate was dissolved in saline and injected subcutaneously at a volume of 5 ml/kg. All the test drugs and MK-801 were prepared on the day of the experiment. All other agents were obtained from commercial sources.[2]

We performed 3 sets of studies as described below.
Study 1:
As previously reported for clozapine and olanzapine (Ninan and Kulkarni, 1996, Rasmussen et al., 2001), some antipsychotic drugs may impair passive-avoidance learning when administered alone before the training session. Therefore, we first investigated the effects of Lurasidone and other antipsychotic drugs on the acquisition of the passive-avoidance response, when administered alone without giving MK-801. Antipsychotic drugs or the vehicle MC was administered orally 1 h before the passive-avoidance training. Ten to 15 rats per dose group were used. The data from this study were used to determine dosages of antipsychotic drugs that did not impair the passive-avoidance response.

Study 2:
We next examined the effect of Lurasidone on MK-801-induced deficits in the passive-avoidance response and compared the results with those of the other antipsychotic drugs. A pre-training injection of MK-801 is known to induce state-dependency in some of the context-dependent responses such as the passive avoidance in rats, which apparently impairs the retrieval of acquired response unless a pre-test injection of MK-801 is also given to rats (Harrod et al., 2001, Jackson et al., 1992, Schmidt et al., 1999). In this study, therefore, we gave both pre-training and pre-test injections of MK-801 to avoid the state-dependent influence with MK-801, according to the procedures as previously used in the passive-avoidance test (Harrod et al., 2001, Nakagawa and Iwasaki, 1996). In addition, a relatively low dose of MK-801 (0.05 mg/kg, s.c.) that reportedly does not affect motor functions and the passive-avoidance retrieval with the pre-test injection (Nakagawa and Iwasaki, 1996, Venable and Kelly, 1990) was employed. The antipsychotic drugs were administered 1 h before the training session at doses that did not impair the passive-avoidance response in Study 1. Twenty to 25 rats per dose group were used.

Study 3:
To investigate the interaction of Lurasidone with MK-801 specifically in the memory consolidation process of acquiring the passive-avoidance response (McGaugh, 1973, McGaugh, 2000), lurasidone was injected intravenously, 10 min after the animals received the foot-shock training and were returned to their home cages. MK-801 was given as described for Study 2. Fifteen animals per dose group were used.

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.

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Hepatotoxicity
Liver test abnormalities occur in 1% to 3% of patients on long term therapy with lurasidone, but similar rates have been reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to lurasidone therapy. Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Lurasidone is more than 99% bound to plasma proteins, so it is unlikely that the drug would be excreted into milk in sufficient amounts to affect a breastfed infant. Data from one mother-infant pair appears to support the poor excretion into milk and lack of effect on the breastfed infant. Until more data are available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.

◉ Effects in Breastfed Infants
A woman with depressive type schizoaffective disorder was taking lurasidone 40 mg at night and desvenlafaxine 50 mg daily after giving birth. She exclusively breastfed her infant. The infant’s growth and development was good during a follow-up period of 39 days.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking lurasidone was not reported.

◉ Effects on Lactation and Breastmilk
Increases in serum prolactin with lurasidone are generally infrequent, small and less than risperidone. A woman with elevated serum prolactin, breast tenderness and galactorrhea while taking risperidone improved when lurasidone was substituted for risperidone and these side effects subsided completely when the lurasidone dose was increased from 20 mg to 40 mg daily. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who had primarily diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking lurasidone was not reported.
A 14-year-old girl with hallucinatory schizophrenia was treated inadequately with aripiprazole, then paliperidone. As she was transitioned from paliperidone to lurasidone at age 16 years, her serum prolactin increased to 4240 mIU/L (normal range 60-400 mIU/L). As the lurasidone dose was titrated to a maximum of 111 mg daily, prolactin levels continued to increase and the patient experienced breast fullness and galactorrhea. Six of 7 serum prolactin measurements were in the range of 4240 to 6140 mIU/L. Once lurasidone was discontinued, her serum prolactin normalized.
In an Italian study of treatment of schizophrenic patients with lurasidone, 2.4% of patients developed hyperprolactinemia and galactorrhea.

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Drugs and Lactation Database (LactMed)
◈ What is lurasidone?
Lurasidone is an antipsychotic medication that has been used to treat schizophrenia and bipolar depression. It is sold under the brand name Latuda®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

◈ I take lurasidone. Can it make it harder for me to get pregnant?
Studies have not been done in humans to see if lurasidone can make it harder to get pregnant.

◈ Does taking lurasidone increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Studies have not been done to see if lurasidone can increase the chance for miscarriage.

◈ Does taking lurasidone increase the chance of birth defects?*
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Information on the use of lurasidone in pregnancy is limited. Animal studies in rats and rabbits have not shown an increased chance of birth defects. In a case report of a person taking lurasidone throughout pregnancy, the baby was born healthy and without birth defects. A study looking at 134 people who used lurasidone in pregnancy found no specific patterns of birth defects.

◈ Does taking lurasidone in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if lurasidone use in pregnancy increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).

◈ I need to take lurasidone throughout my entire pregnancy. Will it cause symptoms in my baby after birth?
Product labels written by the U.S. Food and Drug Administration (FDA) note a chance for symptoms in newborns exposed to antipsychotic drugs in the third trimester of pregnancy. Symptoms may include uncontrolled muscle movements, changes in muscle tone, being too sleepy, trouble with breathing, and/or trouble with feeding. Not all babies who are exposed to antipsychotic drugs during pregnancy will have these symptoms. These symptoms can be temporary and can go away on their own. Treatment of symptoms can be started, if needed.These symptoms have not been reported with exposure to lurasidone during pregnancy. The available information on the use of lurasidone in pregnancy is so limited that it is hard to know if these symptoms might happen. Let your healthcare providers know before delivery if you are taking lurasidone. If needed, babies can be monitored for symptoms.

◈ Does taking lurasidone in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if lurasidone use in pregnancy can cause behavior or learning issues for the child.

◈ Breastfeeding while taking lurasidone:
Information on the use of lurasidone while breastfeeding is limited. There is a report of one person who was taking lurasidone while breastfeeding. No negative effects were reported in the nursing child. The benefit of using lurasidone may outweigh possible risks. Your healthcare providers can talk with you about using lurasidone and what treatment is best for you. Be sure to talk to your healthcare provider about all your breastfeeding questions.

◈ If a male takes lurasidone, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done in humans to see if lurasidone could affect fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[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]. Lurasidone (SM-13496), a novel atypical antipsychotic drug, reverses MK-801-induced impairment of learning and memory in the rat passive-avoidance test. Eur J Pharmacol. 2007 Oct 31;572(2-3):160-70.

[3]. The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions. Pharmacol Rep. 2020 Dec;72(6):1685-1694.

[4]. 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.

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Lurasidone hydrochloride is a hydrochloride obtained by reaction of lurasidone with one equivalent of hydrochloric acid. An atypical antipsychotic agent used for the treatment of schizophrenia. It has a role as a dopaminergic antagonist, a serotonergic antagonist, an adrenergic antagonist and a second generation antipsychotic. It contains a lurasidone(1+).
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 (has active moiety).

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Drug Indication
Treatment of schizophrenia in adults aged 18 years and over.
Treatment of schizophrenia.

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Lurasidone [(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; SM-13496] is an azapirone derivative and a novel antipsychotic candidate. The objective of the current studies was to investigate the in vitro and in vivo pharmacological properties of lurasidone. Receptor binding affinities of lurasidone and several antipsychotic drugs were tested under comparable assay conditions using cloned human receptors or membrane fractions prepared from animal tissue. Lurasidone was found to have potent binding affinity for dopamine D(2), 5-hydroxytryptamine 2A (5-HT(2A)), 5-HT(7), 5-HT(1A), and noradrenaline alpha(2C) receptors. Affinity for noradrenaline alpha(1), alpha(2A), and 5-HT(2C) receptors was weak, whereas affinity for histamine H(1) and muscarinic acetylcholine receptors was negligible. In vitro functional assays demonstrated that lurasidone acts as an antagonist at D(2) and 5-HT(7) receptors and as a partial agonist at the 5-HT(1A) receptor subtype. Lurasidone showed potent effects predictive of antipsychotic activity, such as inhibition of methamphetamine-induced hyperactivity and apomorphine-induced stereotyped behavior in rats, similar to other antipsychotics. Furthermore, lurasidone had only weak extrapyramidal effects in rodent models. In animal models of anxiety disorders and depression, treatment with lurasidone was associated with significant improvement. Lurasidone showed a preferential effect on the frontal cortex (versus striatum) in increasing dopamine turnover. Anti-alpha(1)-noradrenergic, anticholinergic, and central nervous system (CNS) depressant actions of lurasidone were also very weak. These results demonstrate that lurasidone possesses antipsychotic activity and antidepressant- or anxiolytic-like effects with potentially reduced liability for extrapyramidal and CNS depressant side effects. [1]

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Background
The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes).
Methods
The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3-N-demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N-demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC.
Results
Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism (Ki = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism (Ki = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 (Ki = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 (Ki = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 (Ki = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism (Ki = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism (Ki = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity (Ki = 37.5 and 85 µM in microsomes and supersomes).
Conclusion
The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.[3]

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; Lurasidone; 367514-87-2; lurasidona; (3aR,4S,7R,7aS)-2-((1R,2R)-2-(4-(1,2-Benzothiazol-3-yl)piperazin-1-ylmethyl)cyclohexylmethyl)hexahydro-4,7-methano-2H-isoindole-1,3-dione; lurasidonum; UNII-22IC88528T; CHEBI:70735; HSDB 8228; 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.)