ENDOXIFEN FOR THE TREATMENT OF BIPOLAR I DISORDER

Abstract

A method for managing or decreasing a risk of suicidal behaviour in a patient undergoing treatment of bipolar I disorder is provided. The said method includes maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days.

Claims

1. A method for managing or decreasing a risk of suicidal behavior in a patient undergoing treatment of bipolar I disorder comprising: maintaining a therapeutically effective concentration of endoxifen in the patient by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days.

2. The method of claim 1, wherein the patient has manic episodes with mixed features.

3. The method of claim 1, wherein the patient has manic episodes without mixed features.

4. The method of claim 1, wherein the patient has depression.

5. The method of claim 1, wherein the patient associated with depressive episodes.

6. The method of claim 1, wherein the patient had the bipolar I disorder progress during or after treatment with at least one drug(s) selected from lithium, valproate, carbamazepine or an antipsychotic.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0024] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0025] For the purposes of the present disclosure, any ranges given include both the lower and the upper end points of the range. Ranges given should be considered approximate, unless specifically stated.

[0026] The term “C-SSRS” refers to Columbia-Suicide Severity Rating Scale.

[0027] The term “PP population” refers to per protocol population to those population who completed the study without major protocol violations/deviations.

[0028] The term “EOT” refers to end of treatment.

[0029] The term “therapeutically effective concentration” refers to a concentration of endoxifen in plasma which is sufficient to decrease or prevent or cure the symptoms associated with a medical condition or infirmity or to normalize body functions in disease or disorders that result in impairment of specific bodily functions.

[0030] The term “enteric coating” refers to any pharmaceutically acceptable coating preventing the release of the active agent in the stomach and sufficiently disintegrating in the intestine tract (by contact with approximately neutral or alkaline intestine juices) to allow the resorption of the active agent through the walls of the intestinal tract. The enteric coating remains intact in the acidic environment of the stomach and then solubilize in the more alkaline environment of the small intestine. Generally speaking, enteric coating helps in preventing gastric mucosal irritation and can be used for acid labile drugs which gets denatured in acidic medium.

[0031] In one embodiment the present application provides a method for maintaining a therapeutically effective concentration of endoxifen for treatment of bipolar I disorder in a patient.

[0032] In another embodiment, the present application provides a method for maintaining a therapeutically effective concentration of endoxifen for treatment of bipolar I disorder in a patient, wherein the patient has manic episodes with or without mixed features.

[0033] In another embodiment the present application provides a method for maintaining a therapeutically effective concentration of endoxifen for treatment of bipolar I disorder in a patient, wherein the patient has depression or associated with depressive episodes.

[0034] In another embodiment the present application provides a method for maintaining a therapeutically effective concentration of endoxifen for the treatment of patient with bipolar I disorder, wherein the method comprises administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof.

[0035] In another embodiment the present application provides a method for maintaining a therapeutically effective concentration of endoxifen for the treatment of patient with bipolar I disorder, wherein the method comprises administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof.

[0036] In another embodiment the present application provides a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof.

[0037] In another embodiment the present application provides a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof, wherein the risk of suicidal behavior in a patient is substantially less.

[0038] In another embodiment the present application provides a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof, wherein the risk of suicidal behavior in a patient is zero.

[0039] In another embodiment the present application provides a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof and that has progressed during or after treatment with at least one drug(s) selected from lithium, valproate, carbamazepine or an antipsychotic.

[0040] In another embodiment the present application provides a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof and that has progressed during or after treatment with at least one drug(s) selected from lithium, valproate, carbamazepine or an antipsychotic, wherein the risk of suicidal behavior in a patient is substantially less.

[0041] In another embodiment the present application provides a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof and that has progressed during or after treatment with at least one drug(s) selected from lithium, valproate, carbamazepine or an antipsychotic, wherein the risk of suicidal behavior in a patient is zero.

[0042] The embodiments disclosed herein are directed to a method for managing or decreasing a risk of suicidal behavior in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen by administrating a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days to patient in need thereof.

[0043] The embodiments described herein have been described by way of example only, and it is to be recognized that modifications thereto falling within the scope, and spirit of appended claims, and which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be within the scope of this application.

[0044] Clinical Study Data:

[0045] Clinical study of an enteric coated tablet comprising endoxifen citrate formulation was carried out by administering to the patient doses of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days according to the present application.

[0046] Design of the Study:

[0047] This study was a multicenter, randomized, double-blind, double-dummy, active controlled, parallel study to assess the efficacy and safety of endoxifen enteric coated tablet 8 mg and divalproex sodium extended release tablet 1000 mg in patient of bipolar I disorders, this study also evaluated the risk of suicidal behavior in the patient and that has progressed during or after treatment with at least one drug(s) selected from lithium, valproate, carbamazepine or an atypical (except clozapine) or typical antipsychotic.

[0048] Total 110 patients were qualified for PP population.

[0049] The clinical trial study results are incorporated with different parameters as below,

TABLE-US-00001 TABLE 1 Proportion of patients with C-SSRS score at each visit (PP population) Day/Visit Questions Results T (N = 110) p-value Day 0 Q. 1 YES 0 (0.00%) — NO 110 (100.00%) Q. 2 YES 0 (0.00%) — NO 110 (100.00%) Day 7 Q. 1 YES 0 (0.00%) — NO 110 (100.00%) Q. 2 YES 0 (0.00%) — NO 110 (100.00%) Day 14 Q. 1 YES 0 (0.00%) — NO 110 (100.00%) Q.2 YES 0 (0.00%) — NO 110 (100.00%) Day 21 Q. 1 YES 0 (0.00%) — NO 110 (100.00%) Q. 2 YES 0 (0.00%) — NO 110 (100.00%) Treatment Specification: T-> Test Product. Note 1: Percentages are calculated based on the total number of patients in each treatment. Note 2: Q. 1 - Have you wished you were dead or wished you could go to sleep and not wake up ? Q. 2 - Have you actually had any thoughts of killing yourself ? p-value could not be calculated as there is no data for response YES in Q. 1 and Q. 2

[0050] At day 21 (EOT), endoxifen yielded the risk of suicidal behavior is zero in patient with bipolar I disorders.

[0051] Suicidal behavior was not reported during the clinical study.