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Iloperidone

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ACTIVE PHARMA INGREDIENTS

13 API Suppliers, 8 USDMF, 3 EU WC, 7 NDC API, 6 Listed Suppliers

13 API Suppliers
8 USDMF
3 EU WC
7 NDC API
6 Listed Suppliers

DEVELOPMENTS

2 Drugs in Development

2 Drugs in Development

INTERMEDIATES

8 Intermediate Suppliers

8 Intermediate Suppliers

FINISHED DOSAGE FORMULATIONS

68 FDF Dossiers, 33 FDA Orange Book, 35 Listed Dossiers

68 FDF Dossiers
33 FDA Orange Book
35 Listed Dossiers

DRUG PRODUCT COMPOSITIONS

TABLET;ORAL - 10MG, TABLET;ORAL - 12MG, TABLET;ORAL - 1MG, TABLET;ORAL - 2MG, TABLET;ORAL - 4MG, TABLET;ORAL - 6MG, TABLET;ORAL - 8MG

drugProductComposition
TABLET;ORAL - 10MG
TABLET;ORAL - 12MG
TABLET;ORAL - 1MG
TABLET;ORAL - 2MG
TABLET;ORAL - 4MG
TABLET;ORAL - 6MG
TABLET;ORAL - 8MG

RELATED EXCIPIENT COMPANIES

2 SPI Pharma, 1 DKSH, 2 Faran Shimi Pharmaceutical, 4 Boai NKY Pharmaceuticals Ltd, 8 Gangwal Healthcare, 1 Nanjing Well Pharmaceutical, 1 ACG Worldwide, 1 Alcedo Pharmachem, 5 Anhui Sunhere Pharmaceutical Excipients Co.,Ltd, 6 BASF, 10 Corel Pharma Chem, 4 DFE Pharma, 8 Gangwal Chemicals, 5 Ideal Cures Pvt Ltd, 30 Kerry, 3 Kima Chemical, 6 Lonza Capsugel, 11 Microlex e.U, 2 Novo Excipients, 2 Pharmatrans-Sanaq, 2 Pluviaendo, 2 Prachin Chemical, 1 Qianhao Chemical (Hebei) Co., Ltd, 1 Qualicaps, 7 Roquette, 6 Seppic, 3 Shanghai Shenmei Pharmaceutical Technology Co., Ltd, 9 Sigachi Industries, 2 The Dow Chemical Company, 1 Ulanqab Kema New Material, 2 Vasa Pharmachem

EXCIPIENTS BY APPLICATIONS

45 Fillers, Diluents & Binders, 40 Coating Systems & Additives, 26 Direct Compression, 20 Controlled & Modified Release, 17 Disintegrants & Superdisintegrants, 15 Granulation, 15 Thickeners and Stabilizers, 12 Co-Processed Excipients, 11 Lubricants & Glidants, 6 Film Formers & Plasticizers, 6 Chewable & Orodispersible Aids, 5 Empty Capsules, 5 API Stability Enhancers, 4 Vegetarian Capsules, 4 Taste Masking, 4 Solubilizers, 4 Emulsifying Agents, 2 Coloring Agents, 2 Rheology Modifiers, 1 Parenteral

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1 US Medicaid Prescriptions

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2 APIs, 2 FDF Dossiers

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2 APIs
2 FDF Dossiers

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63 US Patents, 7 US Exclusivities

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63 US Patents
7 US Exclusivities

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2 USP , 2 Others

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2 USP
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Synopsis

ACTIVE PHARMA INGREDIENTS

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USDMF

CEP/COS

JDMF

EU WC

KDMF

NDC API

VMF

Listed Suppliers

API REF. PRICE (USD/KG)

$ 0

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FDF

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FDF Dossiers

FDA Orange Book

Europe

Canada

Australia

South Africa

Listed Dossiers

2DRUGS IN DEVELOPMENT

DRUG PRODUCT COMPOSITIONS

REF. STANDARDS OR IMPURITIES

EDQM

USP

Others

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US Patents

US Exclusivities

Health Canada Patents

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148 RELATED EXCIPIENT COMPANIES

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Chemistry

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Also known as: 133454-47-4, Zomaril, Fanapt, Fanapta, Hp 873, Hp-873

Molecular Formula

C₂₄H₂₇FN₂O₄

Molecular Weight

426.5 g/mol

InChI Key

XMXHEBAFVSFQEX-UHFFFAOYSA-N

FDA UNII

VPO7KJ050N

Iloperidone is an atypical antipsychotic for the treatment of schizophrenia symptoms. Hoechst Marion Roussel Inc. researched the drug until May 1996. In June 1997 they gave the research rights to Titan Pharmaceuticals, who gave the worldwide development, manufacturing, and marketing rights to Novartis in August 1998. On June 9, 2004, Titan Pharmaceuticals gave the Phase III development rights to Vanda Pharmaceuticals. FDA approved on May 9, 2009.

Iloperidone is an Atypical Antipsychotic.

1 2D Structure

Iloperidone

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

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

2.1.2 InChI

InChI=1S/C24H27FN2O4/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

2.1.3 InChI Key

XMXHEBAFVSFQEX-UHFFFAOYSA-N

2.1.4 Canonical SMILES

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

2.2 Other Identifiers

2.2.1 UNII

VPO7KJ050N

2.3 Synonyms

2.3.1 MeSH Synonyms

1. Fanapt

2. Hp 873

3. Hp-873

4. Zomaril

2.3.2 Depositor-Supplied Synonyms

1. 133454-47-4

2. Zomaril

3. Fanapt

4. Fanapta

5. Hp 873

6. Hp-873

7. Iloperidone (fanapt)

8. 4'-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino)propoxy)-3'-methoxyacetophenone

9. 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanone

10. Vpo7kj050n

11. Chembl14376

12. 1-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methoxyphenyl)ethanone

13. Chebi:65173

14. Ethanone, 1-(4-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propoxy)-3-methoxyphenyl)-

15. Ncgc00188864-01

16. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1- Piperidinyl]propoxy]-3-methoxyphenyl]ethanone

17. Dsstox_cid_28986

18. Dsstox_rid_83251

19. Dsstox_gsid_49060

20. 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone

21. Fiapta

22. 1-(4-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl)propoxy)-3-methoxyphenyl)ethanone

23. 1-(4-{3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy}-3-methoxyphenyl)ethanone

24. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

25. Smr002529575

26. Fanapt (tn)

27. Cas-133454-47-4

28. Iloperidone (usan/inn)

29. Unii-vpo7kj050n

30. Iloperidona

31. Iloperidonum

32. Iloperidone [usan:inn:ban]

33. Hsdb 8207

34. Ilo-522

35. Ethanone, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-

36. Iloperidone Solution

37. Iloperidone [mi]

38. Iloperidone [inn]

39. Iloperidone [usan]

40. Gtpl87

41. Iloperidone [vandf]

42. Iloperidone [mart.]

43. Iloperidone [usp-rs]

44. Iloperidone [who-dd]

45. Mls004774132

46. Mls006011943

47. Schembl115755

48. Dtxsid6049060

49. Iloperidone, >=98% (hplc)

50. Iloperidone [orange Book]

51. Bcpp000206

52. Hms3604b21

53. Hms3654j14

54. Hms3884a19

55. Hp873

56. (non-isotopelabelled)iloperidone-d6

57. Act02698

58. Bcp02042

59. Zinc1548097

60. Tox21_113610

61. Bdbm50034043

62. Mfcd00866688

63. Pdsp1_000514

64. Pdsp1_000515

65. Pdsp2_000512

66. Pdsp2_000513

67. S1483

68. Akos005146266

69. Tox21_113610_1

70. Ac-3482

71. Bcp9000774

72. Ccg-268962

73. Cs-1236

74. Db04946

75. Ncgc00188864-02

76. Ncgc00188864-10

77. 1-(4-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-3-methoxyphenyl)ethan-1-one

78. Hy-17410

79. Am20090764

80. Ft-0631148

81. Ft-0670284

82. I0926

83. Sw219279-1

84. D02666

85. Ab01274793-01

86. Ab01274793_02

87. 454i474

88. A806617

89. L001176

90. Sr-01000940095

91. J-503185

92. Q4199443

93. Sr-01000940095-2

94. Z1691545119

95. Iloperidone, United States Pharmacopeia (usp) Reference Standard

96. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

97. Iloperidone Solution, 1.0 Mg/ml In Methanol, Ampule Of 1 Ml, Certified Reference Material

98. 1-(4-{3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy}-3-methoxyphenyl)ethan-1-one

99. 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone

100. 1-(4-{3-[4-(6-fluoro-benzo[d]isoxazol-3-yl)piperidin-1-yl]propoxy}-3-methoxy-phenyl)-ethanone

101. 1-[4-[3-[4(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone

102. 1-[4-[3-[4-(6-fluoranyl-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxy-phenyl]ethanone

103. 1-[4-[3-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone

104. 1-[4-[3-[4-(6-fluoro-1,2- Benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3- Methoxyphenyl]ethanone

105. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]-3-methoxyphenyl]-ethanone

106. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- Propoxy]-3-methoxyphenyl]-ethanone

107. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone

108. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3methoxyphenyl]-ethanone

109. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxyl]-3-methoxyphenyl]-ethanone

110. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-phenyl]ethanone

111. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl] Ethanone

112. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

113. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxyphenyl]-ethanone

114. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3methoxyphenyl]ethanone

115. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone

116. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

117. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)1-piperidinyl]-propoxy]-3-methoxyphenyl]-ethanone

118. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxyphenyl] Ethanone

119. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-ethanone

120. 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

121. 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone

122. 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-(trideuteriomethoxy)phenyl]ethanone

2.4 Create Date

2005-08-08

3 Chemical and Physical Properties

Molecular Formula	C₂₄H₂₇FN₂O₄
Molecular Weight	426.5 g/mol
XLogP3	4.1
Hydrogen Bond Donor Count	0
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	8
Exact Mass	426.19548551 g/mol
Monoisotopic Mass	426.19548551 g/mol
Topological Polar Surface Area	64.8 Å²
Heavy Atom Count	31
Formal Charge	0
Complexity	586
Isotope Atom Count	0
Defined Atom Stereocenter Count	0
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Information

1 of 2
Drug Name	Fanapt
PubMed Health	Iloperidone (By mouth)
Drug Classes	Antipsychotic
Drug Label	FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3-methoxyacetophenone . Its molecular formula is C24H27FN2...
Active Ingredient	Iloperidone
Dosage Form	Tablet
Route	Oral
Strength	4mg; 12mg; 6mg; 2mg; 10mg; 1mg; 8mg
Market Status	Prescription
Company	Novartis

2 of 2
Drug Name	Fanapt
PubMed Health	Iloperidone (By mouth)
Drug Classes	Antipsychotic
Drug Label	FANAPT is a psychotropic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives. Its chemical name is 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3-methoxyacetophenone . Its molecular formula is C24H27FN2...
Active Ingredient	Iloperidone
Dosage Form	Tablet
Route	Oral
Strength	4mg; 12mg; 6mg; 2mg; 10mg; 1mg; 8mg
Market Status	Prescription
Company	Novartis

4.2 Therapeutic Uses

An atypical, negative symptom antipsychotic agent.

National Library of Medicine, SIS; ChemIDplus Lite Record for Iloperidone (133454-47-4). Available from, as of June 17, 2014: https://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp

Fanapt tablets are indicated for the treatment of adults with schizophrenia. /Included in US product label/

NIH; DailyMed. Current Medication Information for Fanapt (Iloperidone) Tablet Fanapt (Iloperidone) Kit (Revised: April 2014). Available from, as of July 1, 2014: https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=43452bf8-76e7-47a9-a5d8-41fe84d061f0

4.3 Drug Warning

/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.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2523

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.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2522

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.

4.4 Drug Indication

Treatment of acute schizophrenia.

FDA Label

Treatment of schizophrenia

5 Pharmacology and Biochemistry

5.1 Pharmacology

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 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 NE1 receptors. Furthermore, iloperidone binds with weak affinity to serotonin 5-HT1A, dopamine D1, and histamine H1 receptors.

5.2 MeSH Pharmacological Classification

Antipsychotic Agents

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus. (See all compounds classified as Antipsychotic Agents.)

5.3 FDA Pharmacological Classification

5.3.1 Active Moiety

ILOPERIDONE

5.3.2 FDA UNII

VPO7KJ050N

5.3.3 Pharmacological Classes

Atypical Antipsychotic [EPC]

5.4 ATC Code

N05AX14

N - Nervous system

N05 - Psycholeptics

N05A - Antipsychotics

N05AX - Other antipsychotics

N05AX14 - Iloperidone

5.5 Absorption, Distribution and Excretion

Absorption

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.

Route of Elimination

Renal (in which <1% of iloperidone is excreted unchanged).

Volume of Distribution

Apparent Vd = 1340-2800 L

Clearance

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.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2524

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 ... .

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2524

5.6 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 NE1A, NE1B, NE1D, and NE2C 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.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2524

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 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]- propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, and 4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxy-a-methylbenzene methanol.

S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560

5.7 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.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2524

5.8 Mechanism of Action

Iloperidone is a dopamine D2 and 5-HT2A receptor antagonist and acts as a neuroleptic agent.

Iloperidone is a piperidinyl-benzisoxazole derivative structurally related to risperidone; the drug has been referred to as an atypical or second-generation antipsychotic agent. Although the exact mechanism of action of iloperidone and other antipsychotic agents in schizophrenia is unknown, it has been suggested that the efficacy of iloperidone is mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine (5-HT2)) receptors.

American Society of Health-System Pharmacists 2014; Drug Information 2014. Bethesda, MD. 2014, p. 2524

Fanapt exhibits high (nM) affinity binding to serotonin 5-HT2A dopamine D2 and D3 receptors, and norepinephrine NEalpha1 receptors (Ki values of 5.6, 6.3, 7.1, and 0.36 nM, respectively). FANAPT has moderate affinity for dopamine D4, and serotonin 5-HT6 and 5-HT7 receptors (Ki values of 25, 43, and 22, nM respectively), and low affinity for the serotonin 5-HT1A, dopamine D1, and histamine H1 receptors (Ki values of 168, 216 and 437 nM, respectively). Fanapt has no appreciable affinity (Ki >1000 nM) for cholinergic muscarinic receptors. Fanapt functions as an antagonist at the dopamine D2, D3, serotonin 5-HT1A and norepinephrine alpha1/alpha2C receptors. The affinity of the FANAPT 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 NEalpha1A, NEalpha1B, NEalpha1D, and NEalpha2C receptors (Ki values of 4.7, 2.7, 8.8, and 4.7 nM respectively).

Iloperidone has demonstrated an interesting monoamine receptor profile in radioligand binding studies, with nanomolar affinity for certain noradrenaline, dopamine, and serotonin receptors. In this study, the agonist/antagonist activity of iloperidone was determined in cell lines expressing recombinant human D(2A), D(3), alpha(2C), 5-HT(1A), or 5-HT(6) receptors. With the exception of 5-HT(6) receptors, these receptors are negatively coupled to cyclase. Thus, after stimulation with forskolin, the agonists dopamine (at D(2A) and D(3)), noradrenaline (at alpha(2C)), or 8-OH-DPAT (at 5-HT(1A)) induced a reduction in cAMP accumulation. Conversely, activation of the 5-HT(6) receptor by 5-HT led to an increase in cAMP accumulation. Iloperidone alone was devoid of significant agonist activity but inhibited the agonist response in all 5 cell lines in a surmountable and concentration-dependent fashion. Iloperidone was most potent at D(3) receptors (pK(B) 8.59 + or - 0.20; n = 6), followed by alpha(2C) (pK(B) 7.83 + or - 0.06; n = 15), 5-HT(1A) (pK(B) 7.69 + or - 0.18; n = 10), D(2A) (pK(B) 7.53 + or - 0.04; n = 11) and 5-HT(6) (pK(B) 7.11 + or - 0.08; n = 11) receptors.

PMID:12818723 Kalkman HO et al; Life Sci 73 (9): 1151-9 (2003)

Iloperidone ... demonstrated a potent antipsychotic profile in several in vitro and in vivo animal models. Iloperidone displaced ligand binding at D2 dopamine receptors (IC50 = 0.11 uM) and displayed a high affinity for serotonin (5-HT2) receptors (IC50 = 0.011 uM) and alpha-1 receptors (IC50 = 0.00037 uM). ...

PMID:7562515 Szewczak MR et al; J Pharmacol Exp Ther 274 (3): 1404-13 (1995)

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