ENDOXIFEN FOR THE TREATMENT OF BIPOLAR I DISORDER

Abstract

A method for managing or decreasing a risk of adverse effects 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. Further, adverse effects of alteration in thyroid functions, and thrombocytopenia can be avoided.

Claims

1. A method for managing or decreasing a risk of adverse effects 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, wherein the said adverse effects being managed or decreased are: 1) Alteration in thyroid functions; and 2) Thrombocytopenia.

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.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0017] 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.

[0018] For the purposes of the present application, any ranges given include both the lower and the upper end points of the range. Ranges given should be considered approximate, unless specifically stated.

[0019] The term “EOT” refers to end of treatment.

[0020] The term “safety population” refers to all randomized patients who received at least one dose of study medication.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] In another embodiment the present application provides a method for managing or decreasing a risk of adverse effects in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen, 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.

[0030] In another embodiment the present application provides a method for managing or decreasing a risk of adverse effects in patient undergoing treatment of bipolar I disorder, wherein the said method comprises maintaining the therapeutically effective concentration of endoxifen, 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, wherein the said adverse effects are alteration in thyroid functions, and thrombocytopenia.

[0031] The embodiments described herein are directed to a method for managing or decreasing a risk of adverse effects in a 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. Further, the said adverse effects as per the present disclosure are alteration in thyroid functions, and thrombocytopenia.

[0032] The present application has 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 disclosure.

[0033] Clinical Study Data:

[0034] 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.

[0035] Design of the Study:

[0036] The clinical 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 patients of bipolar I disorders.

[0037] Total 228 patients were enrolled in the study. All 228 patients were qualified for safety trial.

[0038] The clinical trial study results are incorporated with different parameters as below,

TABLE-US-00001 TABLE 1 Summary of adverse events by system organ class and preferred term (PT) (Safety Population) T R Total System Organ Class (N = 116) (N = 112) (N = 228) Preferred Term n (%) e n (%) e n (%) e Patients with at least one TEAE 32 (27.59%) 48 32 (28.57%) 52 64 (28.07%) 100 Blood and lymphatic system disorders 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Leukopenia 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Gastrointestinal disorders  9 (7.76%) 13 11 (9.82%) 13 20 (8.77%) 26 Abdominal Pain 1 (0.86%) 1 3 (2.68%) 3 4 (1.75%) 4 Abdominal Pain Upper 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Constipation 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Diarrhoea 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Epigastric Discomfort 1 (0.86%) 1 1 (0.89%) 1 2 (0.88%) 2 Gastritis 2 (1.72%) 2 0 (0.00%) 0 2 (0.88%) 2 Gastrooesophageal Reflux Disease 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Nausea 1 (0.86%) 1 1 (0.89%) 1 2 (0.88%) 2 Toothache 1 (0.86%) 1 1 (0.89%) 1 2 (0.88%) 2 Vomiting 5 (4.31%) 6 4 (3.57%) 4  9 (3.95%) 10 General disorders and administration site conditions 1 (0.86%) 1 7 (6.25%) 7 8 (3.51%) 8 Chest Pain 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Fatigue 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Pain 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Pyrexia 1 (0.86%) 1 4 (3.57%) 4 5 (2.19%) 5 Hepatobiliary disorders 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Liver Disorder 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Infections and infestations 2 (1.72%) 2 2 (1.79%) 2 4 (1.75%) 4 Hordeolum 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Nasopharyngitis 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Upper Respiratory Tract Infection 1 (0.86%) 1 1 (0.89%) 1 2 (0.88%) 2 Investigations 1 (0.86%) 1 2 (1.79%) 3 3 (1.32%) 4 Blood Pressure Decreased 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Blood Thyroid Stimulating Hormone Increased 0 (0.00%) 0 2 (1.79%) 2 2 (0.88%) 2 Platelet Count Decreased 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Metabolism and nutrition disoders 0 (0.00%) 0 2 (1.79%) 2 2 (0.88%) 2 Decreased Appetite 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Hypertriglyceridemia 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Musculoskeletal and connective tissue disorders 1 (0.86%) 1 1 (0.89%) 1 2 (0.88%) 2 Back Pain 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Flank Pain 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Nervous system disorders 10 (8.62%) 13 11 (9.82%) 14 21 (9.21%) 27 Dizziness 0 (0.00%) 0 5 (4.46%) 6 5 (2.19%) 6 Headache  9 (7.76%) 12 4 (3.57%) 5 13 (5.70%) 17 Paraesthesia 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Somnolence 1 (0.86%) 1 2 (1.79%) 2 3 (1.32%) 3 Psychiatric disorders 10 (8.62%) 14 7 (6.25%) 9 17 (7.46%) 23 Anxiety 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Depression 2 (1.72%) 2 0 (0.00%) 0 2 (0.88%) 2 Insomnia 4 (3.45%) 4 5 (4.46%) 5 9 (3.95%) 9 Mania 4 (3.45%) 4 1 (0.89%) 1 5 (2.19%) 7 Restlessness 3 (2.59%) 3 0 (0.00%) 0 3 (1.32%) 3 Social Avoidant Behaviour 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Renal and urinary disorders 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Dysuria 0 (0.00%) 0 1 (0.89%) 1 1 (0.44%) 1 Skin and subcutaneous tissue disorders 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 Pruritus 1 (0.86%) 1 0 (0.00%) 0 1 (0.44%) 1 n = Number of Patient in respective categories; e = Number of events. Percentages are calculated based on the total number of patients in each treatment. Each patient is counted at the most once within each PT. Adverse Events are coded using Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 Treatment specification: T−> Test Product and R−> Reference Product

TABLE-US-00002 TABLE 2 Summary adverse events by relationship to study drug and system organ class and PT (Safety Population) T R (N = 116) (N = 112) System Organ Class n (%) e n (%) e Preferred Term Related Not-Related Related Not-Related Patients with at least one TEAE 22 (18.97%) 37 10 (8.62%) 11 21 (18.75%) 38 11 (9.82%) 14 Blood and lymphatic system disorders 0 (0.00%) 0 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 Leukopenia 0 (0.00%) 0 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 Gastrointestinal disorders  8 (6.90%) 10 3 (2.59%) 3 7 (6.25%) 8 5 (4.46%) 5 Abdominal pain 1 (0.86%) 1 0 (0.00%) 0 3 (2.68%) 3 0 (0.00%) 0 Abdominal pain upper 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Constipation 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Diarrhoea 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Epigastric discomfort 1 (0.86%) 1 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Gastritis 1 (0.86%) 1 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 Gastrooesophageal reflux disease 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Nausea 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Toothache 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Vomiting 4 (3.45%) 4 2 (1.72%) 2 3 (2.68%) 3 1 (0.89%) 1 General disorders and administration site conditions 1 (0.86%) 1 0 (0.00%) 0 4 (3.57%) 4 3 (2.68%) 3 Chest pain 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Fatigue 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Pain 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Pyrexia 1 (0.86%) 1 0 (0.00%) 0 3 (2.68%) 3 1 (0.89%) 1 Hepatobiliary disorders 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Liver disorder 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Infections and infestations 1 (0.86%) 1 1 (0.86%) 1 0 (0.00%) 0 2 (1.79%) 2 Hordeolum 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Nasopharyngitis 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Upper respiratory tract infection 0 (0.00%) 0 1 (0.86%) 1 0 (0.00%) 0 1 (0.89%) 1 Investigations 1 (0.86%) 1 0 (0.00%) 0 2 (1.79%) 3 0 (0.00%) 0 Blood pressure decreased 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Blood thyroid stimulating hormone increased 0 (0.00%) 0 0 (0.00%) 0 2 (1.79%) 2 0 (0.00%) 0 Platelet count decreased 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Metabolism and nutrition disoders 0 (0.00%) 0 0 (0.00%) 0 2 (1.79%) 3 0 (0.00%) 0 Decreased appetite 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Hypertriglyceridemia 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Musculoskeletal and connective tissue disorders 1 (0.86%) 1 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Back pain 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Flank pain 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Nervous system disorders  7 (6.03%) 10 3 (2.59%) 3  9 (8.04%) 12 2 (1.79%) 2 Dizziness 0 (0.00%) 0 0 (0.00%) 0 5 (4.46%) 6 0 (0.00%) 0 Headache 6 (5.17%) 9 3 (2.59%) 3 3 (2.68%) 4 1 (0.89%) 1 Paraesthesia 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Somnolence 1 (0.86%) 1 0 (0.00%) 0 2 (1.79%) 2 0 (0.00%) 0 Psychiatric disorders  9 (7.76%) 12 2 (1.72%) 2 5 (4.46%) 7 2 (1.79%) 2 Anxiety 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 Depression 1 (0.86%) 1 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 Insomnia 4 (3.45%) 4 0 (0.00%) 0 4 (3.57%) 4 1 (0.89%) 1 Mania 4 (3.45%) 4 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Restlessness 3 (2.59%) 3 0 (0.00%) 0 0 (0.00%) 0 0 (0.00%) 0 Social avoidant behaviour 0 (0.00%) 0 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 Renal and urinary disorders 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Dysuria 0 (0.00%) 0 0 (0.00%) 0 1 (0.89%) 1 0 (0.00%) 0 Skin and subcutaneous tissue disorders 0 (0.00%) 0 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 Pruritus 0 (0.00%) 0 1 (0.86%) 1 0 (0.00%) 0 0 (0.00%) 0 n = Number of Patient in respective categories; e = Number of events. Percentages are calculated based on the total number of patients in each treatment. Each patient is counted at the most once within each PT. Adverse Events are coded using Medical Dictionary for Regulatory Activities (MedDRA) version 20.1 Related = related, probable/Likely, possible. Not Related = unrelated, unlikely. Treatment specification: T−> Test Product and R−> Reference Product

[0039] At the EOT, none of the patients have an alteration in thyroid functions and thrombocytopenia and none of the patients discontinue from the study.