Rat D2 Receptor ( Ki = 54 nM ); Rat 5-HT2 Receptor ( Ki = 3.1 nM ); Rat D1 Receptor ( Ki = 546 nM ); Rat 5-HT1A Receptor ( Ki = 168 nM ); Rat 5-HT6 Receptor ( Ki = 42.7 nM ); Rat 5-HT7 Receptor ( Ki = 21.6 nM ); Human D1 Receptor ( Ki = 216 nM ); Human D3 Receptor ( Ki = 7.1 nM ); Human D4 Receptor ( Ki = 25 nM ); Human D5 Receptor ( Ki = 319 nM ); Human 5-HT2A Receptor ( Ki = 5.6 nM ); Human 5-HT2C Receptor ( Ki = 42.8 nM )

Iloperidone hydrochloride has a higher affinity for the dopamine D3 receptor (Ki = 7.1 nM) than the dopamine D4 receptor (Ki = 25 nM). Iloperidone has a high affinity for the 5-HT6 and 5-HT7 receptors (Ki=42.7 and 21.6 nM, respectively), and a higher affinity for the 5-HT2A receptor (Ki=5.6 nM) than the 5-HT2C receptor (Ki=42.8 nM)[1].

The elimination of iloperidone hydrochloride is sluggish, taking an average of 13.5 to 14.0 hours. AUC, tmax, and Cmax were not significantly impacted by coadministration with meals. These findings suggest that taking iloperidone with meals slows down the drug's absorption rate while maintaining the same level of total bioavailability. The most often reported side effects were somnolence, dizziness, and orthostatic hypotension[2].

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In vivo studies: effects of Iloperidone in animal models [3]
A series of behavioural pharmacology studies were conducted in different animals Citation.
Iloperidone affinity for the dopamine and noradrenaline receptors was confirmed in vivo: the drug demonstrated to be able to prevent the prepulse inhibition-disruptive effect of apomorphine (a direct dopamine receptor agonist) and cirazoline (a α1 receptor agonist) Citation.

The potential efficacy of iloperidone as an antipsychotic was demonstrated in several behavioural assays including antagonised apomorphine-induced climbing behaviour in mice, pole climb avoidance in rats and continuous avoidance responding behaviour in monkeys Citation. Potential efficacy of iloperidone against negative symptoms of schizophrenia was demonstrated by a series of experiments conducted in rodents. Iloperidone, like other atypical antipsychotics, was able to increase social behaviour in unfamiliar rats, a property not observed when testing classical neuroleptics such as haloperidol Citation. Positive results were obtained in the rat-elevated plus maze assay Citation, suggestive of an anxiolytic profile of iloperidone.

More recently, the effect of iloperidone on working memory of rats was examined and compared with the effects of clozapine and haloperidol using a ‘delayed non-matching-to-position’ paradigm. The study demonstrated that iloperidone, differently from haloperidol and clozapine, was able to improve choice accuracy in rats (suggestive of a positive effect on working memory), although an impaired task performance was obtained Citation.

In vivo experiments were carried out to demonstrate iloperidone's low tendency for causing EPS Citation. Iloperidone, compared with risperidone and haloperidol, resulted much less potent in causing catalepsy (ED50 = 30.7 mg/kg for iloperidone; ED 50 = 0.65 mg/kg for haloperidol and ED50 = 5.7 mg/kg for risperidone). Iloperidone was also much less potent in preventing apomorphine-induced stereotyped behaviour (ED50 = 34.8 mg/kg for iloperidone; ED50 = 0.6 mg/kg for haloperidol and ED50 = 3.2 mg/kg for risperidone). Both assays can be used to evaluate EPS liability; in fact, it should be noted that clozapine does not present cataleptic activity and does not inhibit apomorphine-induced stereotyped behaviour even at toxic doses.

Receptor binding assays [1]
All assays were conducted at 37°C in a Tris buffer containing salts (50 mM Tris buffer, pH 7.7; 120 mM NaCl; 5 mM KCl; 2 mM CaCl2; 1 mM MgCl2), with the exception of the 5-HT2C receptor assay where a different buffer was used (50 mM Tris, 4 mM CaCl2 and 1% ascorbate, pH 7.4). Various binding parameters (ligand, ligand concentration, incubation times, ligand Kd values, displacing agent to define specific binding and tissue/cell line used) are summarized in Table 1. Except where indicated, all binding parameters were optimized at Hoechst Marion Roussel; ligand Kd values were determined using both saturation analysis (Scatchard) as well as kinetic analysis (association and dissociation rates). Membranes from rat tissues were freshly prepared; cell membranes (previously prepared and frozen) were rapidly thawed. Membranes were diluted to an appropriate concentration (between 50–500 μg protein/assay point depending on receptor expression level) in Tris buffer and homogenized.

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CYP2D Enzyme Activity in Brain and Liver Microsomes [4]
The CYP2D activity was determined using the CYP2D specific reaction, i.e., 1′-hydroxylation of bufuralol in microsomes prepared from the brains or livers of control rats (Experiment I) and Iloperidone-treated animals (Experiment II), as described previously. The metabolism of bufuralol was investigated in terms of the linear dependence of product formation on time, substrate and protein concentration.
In Experiment I (inhibition studies), the experiments were performed on the brain microsomes from the whole brain (2 mg of protein/mL) or liver microsomes (0.5 mg of protein/mL) obtained from control rats. The specific reaction, i.e., 1′-hydroxylation of bufuralol, proceeded at the substrate concentrations of 50, 100 and 200 µM for brain microsomes or 5, 10 and 20 µM for liver microsomes, in the absence or presence of in vitro added Iloperidone (1–250 µM for liver microsomes or 25–500 µM for brain microsomes), and was studied under the in vitro conditions described below.
In the study with Iloperidone-treated animals (Experiment II), the bufuralol 1′-hydroxylation reaction proceeded in a system containing brain microsomes derived from selected brain structures of 1–3 rats (ca. 0.4 mg of protein/mL for the nucleus accumbens, 0.7 mg of protein/mL for the hippocampus and the substantia nigra, 1.2 mg of protein/mL for the hypothalamus, 1.5 mg of protein/mL for the striatum, the brain stem and the cerebellum and 2 mg of protein/mL for the frontal cortex and remainder of the brain) or liver microsomes (0.5 mg of protein/mL), potassium phosphate buffer (2 mM, pH = 7.4), NADP (1.6 mM), MgCl2 (4 mM), glucose 6-phosphate (5 mM) and glucose 6-phosphate-dehydrogenase (2.5 U in every sample), as described earlier.. Bufuralol was added to the incubation medium containing brain microsomes at a concentration of 125 µM or liver microsomes at a concentration of 10 µM to the final volume of 0.4 mL. The total level of microsomal protein was measured by the method of Lowry et al. using bovine serum albumin as a standard.
In all experiments, the amount of 1′-hydroxybufuralol formed from bufuralol was measured by an HPLC method with fluorometric detection.

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Evaluation of CYP2D Protein in Brain and Liver Microsomes [4]
The CYP2D protein levels in microsomes from the brains and livers of control and Iloperidone-treated animals were quantified by Western blotting, as previously described. Briefly, microsomal proteins (10 μg of brain and liver microsomes per each sample) were separated using an SDS polyacrylamide gel electrophoresis, and then the protein bands were transferred onto nitrocellulose membranes. The polyclonal rabbit anti-rat CYP2D4 antibody and polyclonal rabbit anti-human CYP2D6 antibody were used as the primary antibodies for CYP2D4 in brain microsomes and CYP2D enzymes in liver microsomes, respectively. Horseradish peroxidase-labeled goat anti-rabbit IgG was used as a secondary antibody. For the estimation of β-actin level, the primary mouse polyclonal anti-rat β-actin antibody and goat anti-mouse antibody were used. Rat cDNA-expressed CYP2D4 (2.5 µg) and human CYP2D6 (1 µg) were used as standards. The band intensity of the CYP2D protein was evaluated with the Luminescent Image Analyzer LAS-1000 and Image Gauge 3.11 programs. The collected data were normalized to protein loading based on the β-actin levels.

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Iloperidone (HP 873) is an atypical antipsychotic that works as a D2/5-HT2 receptor antagonist to treat symptoms of schizophrenia. Compared to the dopamine D4 receptor (Ki = 25 nM), Iloperidone exhibited a greater affinity for the dopamine D3 receptor (Ki = 7.1 nM). Iloperidone was found to have a higher affinity for the 5-HT2A receptor (Ki = 5.6 nM) than for the 5-HT2C receptor (Ki = 42.8 nM), and to have a high affinity for both the 5-HT6 and 5-HT7 receptors (Ki = 42.7 and 21.6 nM, respectively).

Animal Treatment and Preparation of Brain and Liver Microsomes [4]
To differentiate between the direct effect of Iloperidone on the activity of CYP2D and changes evoked by their chronic in vivo treatment, two experimental approaches were applied. To study the direct effect on the CYP2D protein (inhibition), iloperidone was added in vitro to control brain or liver microsomes (Experiment I). To study the possible influence of iloperidone on CYP2D expression, the drug was administered to rats in vivo for two weeks (Experiment II).

Rats (n = 12) were injected intraperitoneally once a day with a pharmacological dose of Iloperidone(1 mg/kg ip.) or vehicle (1% Tween 80 in sterile water) for a period of two weeks. The dose administered was consistent with previous pharmacological studies on rats, and the dose was active in neurochemical and behavioral paradigms. Rats were killed by decapitation 24 h after the last dose. Brains and livers were removed and the selected brain structures (in accordance with the Paxinos and Watson atlas), receiving dopaminergic and/or serotonergic innervation (the nucleus accumbens, frontal cortex, substantia nigra, striatum, hippocampus, hypothalamus, brain stem, cerebellum, and the remainder of the brain), were isolated and frozen in dry ice and stored at −80 °C until use. Microsomal fraction from the whole control brains, selected brain structures or livers was prepared by differential centrifugation, according to Hiroi et al. and Haduch et al. Brain microsomes were immediately used to determine CYP2D activity, while those of liver microsomes were stored at −80 °C until use.

Absorption, Distribution and Excretion
Well absorbed from the GI tract and Cmax is reached within 2-4 hours. Steady-state concentration is achieved in 3-4 days post-administration of iloperidone. Relative bioavailability of the tablet formulation compared to oral solution is 96%. Accumulation occurs in a predictable fashion.
Renal (in which <1% of iloperidone is excreted unchanged).
Apparent Vd = 1340-2800 L
Apparent clearance (clearance/bioavilability) = 47-102 L/h.
Iloperidone has an apparent clearance (clearance/bioavailability) of 47 to 102 L/hr, with an apparent volume of distribution of 1340 to 2800 L. At therapeutic concentrations, the unbound fraction of iloperidone in plasma is approximately 3% and of each metabolite (P88 and P95) it is approximately 8%.
The majority of radiolabeled iloperidone was recovered in the urine (mean 58.2% and 45.1% in extensive and poor metabolizers of CYP2D6, respectively), with feces accounting for 19.9% (extensive metabolizers) and 22.1% (poor metabolizers) of the radiolabeled dose.
Iloperidone is well absorbed after administration of the tablet with peak plasma concentrations occurring within 2 to 4 hours; while the relative bioavailability of the tablet formulation compared to oral solution is 96%. Administration of iloperidone with a standard high-fat meal did not significantly affect the Cmax or AUC of iloperidone, P88, or P95, but delayed Tmax by 1 hour for iloperidone, 2 hours for P88 and 6 hours for P95. Fanapt can be administered without regard to meals.
... The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS ... .

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Metabolism / Metabolites
Iloperidone is hepatically metabolized by cytochrome enzymes which mediates O-dealkylation (CYP3A4), hydroxylation (CYP2D6), and decarboxylation/reduction processes. Metabolites formed are P89, P95, and P88. The minor metabolite is P89, whereas P95 and P88 are the major ones. The affinity of the iloperidone metabolite P88 is generally equal or less than that of the parent compound. In contrast, the metabolite P95 only shows affinity for 5-HT2A (Ki value of 3.91) and the NEα1A, NEα1B, NEα1D, and NEα2C receptors (Ki values of 4.7, 2.7, 8.8 and 4.7 nM respectively).
Iloperidone is primarily metabolized by carbonyl reduction, cytochrome P-450 (CYP) isoenzyme 2D6-mediated hydroxylation, and CYP3A4-mediated O-demethylation; the drug's two principal metabolites, P88 and P95, undergo further oxidation and/or conjugation with glucuronic acid. The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug.
Iloperidone is metabolized primarily by 3 biotransformation pathways: carbonyl reduction, hydroxylation (mediated by CYP2D6) and O-demethylation (mediated by CYP3A4). There are 2 predominant iloperidone metabolites, P95 and P88. The iloperidone metabolite P95 represents 47.9% of the AUC of iloperidone and its metabolites in plasma at steady-state for extensive metabolizers (EM) and 25% for poor metabolizers (PM). The active metabolite P88 accounts for 19.5% and 34.0% of total plasma exposure in EM and PM, respectively. Approximately 7% to 10% of Caucasians and 3% to 8% of black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of Fanapt with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3-fold increase in iloperidone plasma exposure, and therefore one-half of the Fanapt dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with EMs and PMs should have their dose reduced by one-half.
Iloperidone has known human metabolites that include 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-a-methylbenzene methanol, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, and 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- propoxy]-3-hydroxyphenyl]ethanone.

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Biological Half-Life
The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18, 26 and 23 hours, respectively, and in poor metabolizers (PM) are 33, 37 and 31 hours, respectively.
The mean elimination half-lives of iloperidone, P88, and P95 are 18, 26, and 23 hours, respectively, in extensive metabolizers of CYP2D6 and 33, 37, and 31 hours, respectively, in poor metabolizers of CYP2D6.

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Pharmacokinetics: distribution and metabolism [3]
Iloperidone is well absorbed when administered orally Citation. The pharmacokinetic profile in humans can be depicted from Phase I studies conducted on healthy volunteers Citation. Iloperidone was administered once at 3 or 5 mg. The Cmax observed increased with the dose (2.2 ng/ml for the 3-mg and 5.2 ng/ml for the 5-mg administration), and Tmax values were 2 – 3 h after administration. Elimination was slow, with half-life corresponding to 13.5 – 14 h. Food coadministration did not alter pharmacokinetics significantly. A slight increase in Tmax (from 2.2 to 4.3 h) and Cmax (from 2.3 to 2.0 ng/ml) was observed when iloperidone was administered after food intake, but the bioavailability was unchanged Citation.
In Phase III clinical trials iloperidone was administered in doses from 4 mg/day up to 24 mg/day Citation[70,71]. Lower doses (0.5 – 6 mg/day) were tested out in a clinical trial on elderly patients with dementia Citation.
Iloperidone is highly bound to proteins (93%) in humans over the concentration range 5 – 500 ng/ml; most of the administered dose (orally or intravenously) is recovered in the faeces; therefore, a biliary excretion is likely the main elimination pathway Citation.
Recently, a clinical–chemical correlation was established for iloperidone minimal effective exposure level; it was demonstrated that plasma iloperidone concentration corresponding to 5 ng/ml can be considered the minimal concentration of therapeutic range Citation.

Iloperidone is extensively metabolised to a number of compounds which differ in humans, rats and dogs. Mutlib et al. employed liquid chromatography with mass spectrometry (LC-MS) and NMR detection to identify all the metabolites produced in vitro and in vivo in rats, dogs and humans. In particular, it was found that both in rats and humans the main metabolic pathway was the reduction of the acetophenone ring structure of iloperidone, forming reduced iloperidone (compound I, Figure 2) Citation. This biotransformation is probably primarily mediated by cytosolic enzymes; CYP450 isoforms may be involved as well, as assessed by chemical inhibitor studies Citation. It has been reported that, in dogs, the metabolite reduced iloperidone interconverts to iloperidone Citation; to our best knowledge no data are available regarding the possible role of this reaction in humans. More recently, another compound (metabolite (II), Figure 2) was identified. This is the other main circulating metabolite in humans; it is formed via oxidation and decarboxylation of an α-hydroxy keto metabolite Citation. In humans, both metabolite (I) and (II) reach plasma concentrations higher than the parent compound. Cmax values corresponding to 25 ng/ml for compound (I) and to 40 ng/ml for compound (II) have been reported at the steady-state after administration of iloperidone 16 mg/day (iloperidone Cmax was 20 ng/ml) Citation.

Other metabolites are O-desmethyl iloperidone (compound (III), Figure 2) and 2-hydroxyl iloperidone (compound (IV), Figure 2), formed via CYP3A4 and CYP2D6, respectively Citation[74,76], even if their concentration in biological fluids is much lower in humans. However, it has been shown that in poor CYP2D6 metabolisers, elimination half-life was increased by 88% for iloperidone and 46% for reduced iloperidone Citation.
Further metabolic steps are represented by oxidation and conjugation with glucuronic acid Citation.

Studies have been carried out in order to evaluate the receptor binding profile and the potential therapeutic/side effects of the two most abundant iloperidone metabolites (compounds (I) and (II)). In particular, it was found that reduced iloperidone has a D2 affinity comparable to that of the parent compound, while its affinity for 5-HT2A receptor is 2.5-times lower. Its pharmacokinetic profile similar to that of the parent compound suggests a likely contribution of reduced iloperidone to antipsychotic activity; however, despite its high affinity for 5-HT2A receptors, metabolite (II) does not cross the blood–brain barrier and most probably plays a role in side effects, but not therapeutic efficacy Citation[78]. A study has been carried out to evaluate iloperidone pharmacokinetics in subjects with chronic severe renal impairment or with mild-to-moderate hepatic impairment, after administration of a single dose corresponding to 3 or 2 mg, respectively. As a result, the pharmacokinetic profile of iloperidone and of its main metabolite were not significantly altered in renal or hepatic impaired patients (in the latter group, the exposure to the metabolite was moderately increased) Citation.

Toxicity Summary
IDENTIFICATION AND USE: Ilperidone is a white to off-white finely crystalline powder formulated into oral tablets. Iloperidone is considered an atypical or second-generation antipsychotic agent. It is used for the treatment of adults with schizophrenia. HUMAN EXPOSURE AND TOXICITY: In premarketing trials involving over 3210 patients, accidental or intentional overdose of iloperidone was documented in 8 patients with no fatalities. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension). Elderly patients with dementia-related psychosis treated with iloperidone are at an increased risk of death and therefore iloperidone is not approved for use in that population. Iloperidone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including iloperidone. Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has also been reported in patients receiving atypical antipsychotic agents, including iloperidone. Iloperidone has two predominate metabolites, P88 and P95. The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug. ANIMAL STUDIES: Lifetime carcinogenicity studies were conducted in mice and rats. Iloperidone was administered orally at doses of 2.5, 5.0, and 10 mg/kg/day to mice and up to 16 mg/kg/day to rats. There was an increased incidence of malignant mammary gland tumors in female mice treated with the lowest dose (2.5 mg/kg/day) only. There were no treatment-related increases in neoplasia in rats. The carcinogenic potential of iloperidone metabolite P95 was studied in rats at oral doses up to 200 mg/kg/day in males and up to 250 mg/kg/day in females. Drug-related neoplastic changes occurred in the pituitary gland (pars distalis adenoma) and in the pancreas (islet cell adenoma). Iloperidone also caused developmental toxicity, but was not teratogenic in rats and rabbits. Pregnant rats were given up to 64 mg/kg/day of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. In a similar study, pregnant rabbits were given up to 25 mg/kg of iloperidone during the period of organogenesis. The highest dose caused increased early intrauterine deaths and decreased fetal viability at term; this dose also caused maternal toxicity. Additional studies in rats given iloperidone either pre-conception or from day 17 of gestation and continuing through weaning caused adverse reproductive effects including prolonged pregnancy and parturition, increased stillbirth rates, increased incidence of fetal visceral variations, decreased fetal and pup weights, and decreased post-partum pup survival. There were no drug effects on the neurobehavioral or reproductive development of the surviving pups. Iloperidone decreased fertility at 12 and 36 mg/kg in a study in which both male and female rats were treated. Iloperidone was negative in the Ames test and in the in vivo mouse bone marrow and rat liver micronucleus tests. Iloperidone induced chromosomal aberrations in Chinese Hamster Ovary (CHO) cells in vitro at concentrations which also caused some cytotoxicity.

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Hepatotoxicity
Liver test abnormalities occur in 1% to 3% of patients on long term therapy with iloperidone, but similar rates are reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and usually 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 iloperidone 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
Because no information is available on the use of iloperidone during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
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 iloperidone was not reported.
◉ Effects on Lactation and Breastmilk
Iloperidone causes minimal increases in serum prolactin. 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 iloperidone was not reported.

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Protein Binding
95% of iloperidone is bound to protein. Percent bound is not altered by renal or hepatic impairment or combination therapy with ketoconazole.

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Interactions
Because disruption of body temperature regulation is possible, iloperidone should be used with caution in patients concurrently receiving drugs with anticholinergic activity.
Because of additive effects on QT-interval prolongation, concomitant use of iloperidone with other drugs known to prolong the corrected QT (QTc) interval, including class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, asenapine, olanzapine, paliperidone, pimozide, quetiapine, ziprasidone), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., levomethadyl acetate (no longer commercially available in the US), methadone, pentamidine, tetrabenazine), should be avoided.
Concomitant use of iloperidone with other CNS agents or alcohol may produce additive CNS effects. Caution is advised when iloperidone and other CNS agents are used concomitantly; use of alcohol during iloperidone therapy should be avoided.
Because of its alpha1-adrenergic blocking activity and potential to cause orthostatic hypotension and syncope, the manufacturer recommends that iloperidone be used with caution in patients receiving antihypertensive agents and other drugs that can cause hypotension; monitoring of orthostatic vital signs should be considered in such patients.
For more Interactions (Complete) data for Iloperidone (13 total), please visit the HSDB record page.

[1]. Iloperidone binding to human and rat dopamine and 5-HT receptors. Eur J Pharmacol, 1996. 317(2-3): p. 417-23.

[2]. Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic. J Clin Pharmacol, 1995. 35(7): p. 713-20.

[3]. Iloperidone: a new benzisoxazole atypical antipsychotic drug. Is it novel enough to impact the crowded atypical antipsychotic market? Expert Opin Investig Drugs, 2008. 17(1): p. 61-75.

[4]. Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms. Cells. 2021 Dec 9;10(12):3472.

Therapeutic Uses
An atypical, negative symptom antipsychotic agent.
Fanapt tablets are indicated for the treatment of adults with schizophrenia. /Included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analysis of seventeen placebo-controlled trials (modal duration 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to 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 antipsychotic drugs, treatment with conventional antipsychotic drugs 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 is not clear. Fanapt is not approved for the treatment of patients with dementia-related psychosis.
Geriatric patients with dementia-related psychosis treated with iloperidone are at an increased risk of death compared with those receiving placebo. In addition, 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 the safety and efficacy of iloperidone in the treatment of psychosis associated with Alzheimer's disease have not been established and that the drug is not approved for the treatment of patients with dementia-related psychosis. If a clinician decides to treat such patients with iloperidone, the manufacturer recommends that vigilance be exercised.
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 iloperidone is not approved for the treatment of patients with dementia-related psychosis.
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including Fanapt. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
For more Drug Warnings (Complete) data for Iloperidone (28 total), please visit the HSDB record page.

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Pharmacodynamics
Iloperidone shows high affinity and maximal receptor occupancy for dopamine D2 receptors in the caudate nucleus and putamen of the brains of schizophrenic patients. The improvement in cognition is attributed to iloperidone's high affinity for α adrenergic receptors. Iloperidone also binds with high affinity to serotonin 5-HT2a and dopamine 3 receptors. Iloperidone binds with moderate affinity to dopamine D4, serotonin 5-HT6 and 5-HT7, and norepinephrine NEα1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors.

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Iloperidone (HP 873; 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy] -3- methoxyphenyl]ethanone) is a compound currently in clinical trials for the treatment of schizophrenia. Iloperidone displays affinity for dopamine D2 receptors and for 5-HT2A receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic. Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5-HT receptor subtypes. We employed receptor binding assays using membranes from cells stably expressing human dopamine D1, D2S, D2L, D3, D4 and D5 and 5-HT2A and 5-HT2C receptors and rat 5-HT6 and 5-HT7 receptors. Iloperidone displayed higher affinity for the dopamine D3 receptor (Ki = 7.1 nM) than for the dopamine D4 receptor (Ki = 25 nM). Iloperidone displayed high affinity for the 5-HT6 and 5-HT7 receptors (Ki = 42.7 and 21.6 nM, respectively), and was found to have higher affinity for the 5-HT2A (Ki = 5.6 nM) than for the 5-HT2C receptor (Ki = 42.8 nM). The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds.[1]

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Iloperidone is a new-generation atypical antipsychotic agent, acting as a serotonin/dopamine (5-HT(2A)/D(2)) antagonist, under development by Vanda Pharmaceuticals for the treatment of schizophrenia, bipolar disorder and other psychiatric conditions. Chemically, iloperidone is a benzisoxazole, like risperidone, and shows a multiple receptor binding profile, sharing this feature with the other atypical antipsychotic agents. Administered orally, the drug is highly bound to plasma proteins and extensively metabolised. Several clinical trials have been carried out, to check efficacy, safety and side effects. In order to introduce iloperidone as an agent for the treatment of schizophrenia, a short overview of the disease and of the most important antipsychotic drugs available or under development will be reported. Iloperidone pharmacokinetics and pharmacodynamics are presented herein, together with an evaluation of clinical safety and efficacy results.[3]

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CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 μM and Ki = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.[4]

C24H28CLFN2O4

462.95

462.172

C, 62.27; H, 6.10; Cl, 7.66; F, 4.10; N, 6.05; O, 13.82

1299470-39-5

Iloperidone;133454-47-4;Iloperidone metabolite Hydroxy Iloperidone;133454-55-4

23356600

Typically exists as solid at room temperature

5.566

1

7

8

32

586

0

CC(C1=CC=C(OCCCN2CCC(C3=NOC4=C3C=CC(F)=C4)CC2)C(OC)=C1)=O.Cl

FGACDTCLJARDGD-UHFFFAOYSA-N

InChI=1S/C24H27FN2O4.ClH/c1-16(28)18-4-7-21(23(14-18)29-2)30-13-3-10-27-11-8-17(9-12-27)24-20-6-5-19(25)15-22(20)31-26-24;/h4-7,14-15,17H,3,8-13H2,1-2H3;1H

1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone;hydrochloride

Iloperidone HCl; Iloperidone hydrochloride; 1299470-39-5; Iloperidone (hydrochloride); Iloperidone HCl; HP 873 hydrochloride; Ethanone, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-, hydrochloride (1:1); 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone;hydrochloride; 1-[4-[3-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone Hydrochloride;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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