ENDOXIFEN FOR THE TREATMENT OF BIPOLAR I DISORDER

Abstract

A method for maintaining a therapeutically effective concentration of endoxifen for the treatment of patient with bipolar I disorder is provided. The method includes administering to the patient 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 method provides a desirable in-vivo plasma profile. The therapeutic dose monitoring is not required in a patient undergoing the said treatment. Furthermore, the method provides a significant improvement in mania assessed by the YMRS and the MADRS scores in patient undergoing the said treatment. Furthermore, the method as provides an early response time of the treatment in at least 2 days and remission time that is not more than 4 days in patient undergoing the said treatment.

Claims

1. A method for maintaining a therapeutically effective concentration of endoxifen for treatment of a patient with bipolar I disorder, said method comprising: administering to the patient, a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days, and maintaining an in-vivo plasma profile in the patient including: (a) a mean C.sub.max (ng/mL) of 10 to 180; (b) a mean AUC.sub.0-t (ng.h/mL) of 50 to 3500; and (c) a mean T.sub.max (h) of about 6±2 wherein the therapeutic dose monitoring is not required in a patient who is undergoing treatment with endoxifen citrate.

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

3. The method of claim 1, wherein the patient has manic episodes with 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 of bipolar I disorder has a YMRS score that is less than 25 after the administration of endoxifen citrate to the patient for at least 21 days.

7. The method of claim 1, wherein the patient of bipolar I disorder has a MADRS score that is less than 3 after the administration of endoxifen citrate to the patient for at least 21 days.

8. The method of claim 1, wherein the patient of bipolar I disorder has an early response time of the treatment in at least 2 days and a remission time that is not more than 4 days.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0040] 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.

[0041] 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.

[0042] The term “YMRS” refers to Young Mania Rating Scale.

[0043] The term “MADRS” refers to Montgomery Asberg Depression Rating Scale.

[0044] The term “PP population” refers to per protocol population to those populations who completed the study without major protocol violations/deviations.

[0045] The term “mITT population” refers to modified Intent-To-Treat population to all randomized patients who received at least one dose of study medication and had data of at least one efficacy evaluation.

[0046] The term “EOT” refers to end of treatment.

[0047] 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.

[0048] The term “response time” means an early indicator of treatment efficacy and it is not more than 2 days of treatment according to the embodiments described herein.

[0049] The term “remission time” refers to an absence or minimal symptoms of both mania and depression, which is not more than 4 days of treatment according to the embodiments described herein. Remission is the target of acute treatment.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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 administering to the patient, a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day.

[0055] 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 administering to the patient, a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days.

[0056] 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 administering to the patient, a dose of 2 mg to 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days and maintaining an in-vivo plasma profile in the patient including: [0057] a) a mean C.sub.max (ng/mL) of 10 to 180, [0058] b) a mean AUC.sub.0-t (ng.h/mL) of 50 to 3500, or [0059] c) a mean T.sub.max (h) of 6±2.

[0060] 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 administering to the patient, a dose of 2 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days and maintaining an in-vivo plasma profile in the patient including: [0061] a) a mean C.sub.max (ng/mL) of 10 to 25, [0062] b) a mean AUC.sub.0-t (ng.h/mL) of 50 to 500, or [0063] c) a mean T.sub.max (h) of 6±2.

[0064] 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 administering to the patient, a dose of 4 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days and maintaining an in-vivo plasma profile in the patient including: [0065] a) a mean C.sub.max (ng/mL) of 26 to 60, [0066] b) a mean AUC.sub.0-t (ng.h/mL) of 501 to 1000, or [0067] c) a mean T.sub.max (h) of 6±2.

[0068] 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 administering to the patient, a dose of 8 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days and maintaining an in-vivo plasma profile in the patient including: [0069] a) a mean C.sub.max (ng/mL) of 61 to 100, [0070] b) a mean AUC.sub.0-t (ng.h/mL) of 1001 to 2500, or [0071] c) a mean T.sub.max (h) of 6±2.

[0072] 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 administering to the patient, a dose of 16 mg of endoxifen citrate in an enteric coated tablet once per day for at least 21 days and maintaining an in-vivo plasma profile in the patient including: [0073] a) a mean C.sub.max (ng/mL) of 101 to 180, [0074] b) a mean AUC.sub.0-t (ng.h/mL) of 2501 to 3500, or [0075] c) a mean T.sub.max (h) of 6±2.

[0076] 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 administering to the patient, 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 therapeutic dose monitoring is not required in patient undergoing the said treatment.

[0077] 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 administering to the patient, 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 method provides a significant improvement in mania assessed by the YMRS and the MADRS scores in patient undergoing the said treatment.

[0078] 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 administering to the patient, 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 said method provides a significant improvement in mania assessed by the YMRS and MADRS score, wherein the YMRS score that is less than 25 and the MADRS score that is less than 3 after the treatment of 21 days.

[0079] 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 administering to the patient, 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 said method provides an early response time of the treatment in at least 2 days and remission time that is not more than 4 days in patient undergoing the said treatment.

[0080] The embodiments described herein are directed to a method for maintaining a therapeutically effective concentration of endoxifen for the treatment of patient with bipolar I disorder, wherein the method comprises administering to the patient, 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. Further, the said method provides a desirable an in-vivo plasma profile, and wherein therapeutic dose monitoring is not required in patient undergoing the said treatment. Furthermore, the said method provides a significant improvement in mania assessed by the YMRS and the MADRS scores in patient undergoing the said treatment. Furthermore, the said method provides an early response time of the treatment in at least 2 days and remission time that is not more than 4 days in patient undergoing the said treatment.

[0081] 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.

Clinical Study Data:

[0082] 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.

Design of the Study:

[0083] 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.

[0084] Total 228 patients were enrolled in the study. All 228 patients were qualified for safety and mITT population and 213 patients were qualified for PP population.

[0085] The clinical trial study results are incorporated with different parameters as below,

TABLE-US-00001 TABLE 1 Descriptive statistics for total YMRS score at each visit (PP Population) T R p-value Day Statistics (N = 110) (N = 103) (between) Day 0 n 110 103 0.8229 (baseline) Mean (SD) 32.9 (8.52) 33.1 (8.42) Median 31.0 33.0 Min, Max 20.0, 53.0  20.0, 55.0 Day 2 n 110 103 0.5070 Mean (SD) 30.6 (9.53) 31.3 (8.86) Median 28.5 29.0 Min, Max 13.0, 56.0  17.0, 55.0 p-value <.0001 <.0001 (within) Day 4 n 110 103 0.8316 Mean (SD) 28.6 (9.65) 29.1 (9.13) Median 27.5 27.0 Min, Max 8.0, 56.0 15.0, 55.0 p-value <.0001 <.0001 (within) Day 7 n 110 103 0.9308 Mean (SD)  25.7 (10.01) 25.6 (9.48) Median 25.0 23.0 Min, Max 6.0, 53.0  5.0, 55.0 p-value <.0001 <.0001 (within) Day 14 n 110 103 0.9034 Mean (SD) 21.3 (9.54)  21.5 (10.04) Median 20.0 20.0 Min, Max 2.0, 45.0  1.0, 58.0 p-value <.0001 <.0001 (within) Day 21 n 110 103 0.8858 (EOT) Mean (SD) 16.7 (9.80)  16.7 (10.52) Median 16.0 16.0 Min, Max 0.0, 47.0  0.0, 58.0 p-value <.0001 <.0001 (within) Treatment Specification: T−> Test Product and R−> Reference Product. Note 1: p-value (between) is calculated using Wilcoxon-Rank Sum Test for comparison between Test and Reference treatments. Note 2: p-value (within) is calculated using Wilcoxon signed rank test for comparison of baseline to each visit for each treatment.

[0086] At day 21 (EOT), endoxifen yielded significant and sustained improvements in the YMRS score in patient with bipolar I disorders.

TABLE-US-00002 TABLE 2 Descriptive statistics for MADRS score at each visit (PP Population) T R p-value Day Statistics (N = 110) (N = 103) (between) Day 0 N 110 103 0.9857 (baseline) Mean (SD) 4.7 (3.32) 4.6 (3.02) Median 4.0 4.0 Min, Max 0.0, 14.0  0.0, 12.0 Day 7 N 110 103 0.3815 Mean (SD) 3.2 (2.93) 2.7 (2.31) Median 3.0 2.0 Min, Max 0.0, 13.0 0.0, 9.0 p-value <.0001 <.0001 (within) Day 14 N 110 103 0.6033 Mean (SD) 2.6 (2.92) 2.2 (1.96) Median 2.0 2.0 Min, Max 0.0, 18.0 0.0, 8.0 p-value <.0001 <.0001 (within) Day 21 N 110 103 0.4280 (EOT) Mean (SD) 2.3 (3.70) 1.6 (2.06) Median 1.0 1.0 Min, Max 0.0, 22.0  0.0, 13.0 p-value <.0001 <.0001 (within) Treatment specification: T−> Test Product and R−> Reference Product. Note 1: p-value (between) is calculated using Wilcoxon-Rank Sum Test for comparison between Test and Reference treatments. Note 2: p-value (within) is calculated using Wilcoxon signed rank test for comparison of baseline to each visit for each treatments.

[0087] At day 21 (EOT), endoxifen yielded significant and sustained improvements in the MADRS score in patient with bipolar I disorders.

[0088] From the above table 1 and 2, it is evident that an early response time of the endoxifen treatment in at least 2 days and a remission time of endoxifen treatment is not more than 4 days in patient.

TABLE-US-00003 TABLE 3 Endoxifen pharmacokinetic data Pharmacokinetic Parameter Values Simulated Data 0.5 mg 4 mg 8 mg 16 mg 32 mg Variable Endoxifen Endoxifen Endoxifen Endoxifen Endoxifen T.sub.max (hr) 5.9 ± 1.5 5.3 ± 1.5 5.3 ± 1.5 5.3 ± 1.5 5.3 ± 1.5 C.sub.min (ng/mL) 3.5 ± 0.5 27.4 ± 8.7  54.7 ± 17.3 109.4 ± 34.6  218.8 ± 69.2  C.sub.max (ng/mL) 4.8 ± 0.6 40.5 ± 12.1 80.9 ± 24.2 161.9 ± 48.4  323.9 ± 96.8  C.sub.avg (ng/mL) 4.2 ± 0.6 33.4 ± 10.9 66.7 ± 21.8 133.4 ± 43.7  266.8 ± 87.4  AUC.sub.0-t (ng .Math. h/mL) 99.7 ± 13.7 800.3 ± 262.0 1600.6 ± 524.1  3201.3 ± 1048.1 6402.5 ± 2096.3 Accumulation Index 3.4 ± 1.0 3.8 ± 1.7 3.8 ± 1.7 3.8 ± 1.7 3.8 ± 1.7 wherein, T.sub.max is the time at which the maximum plasma concentration occurs C.sub.min is the minimum plasma concentration C.sub.max is the maximum plasma concentration C.sub.avg is the average plasma concentration AUC.sub.0-t is the area under the plot of drug concentrations versus time curve, from time of drug administration (time “0”) to time “t.”

[0089] Therapeutic dose monitoring was not required during the clinical study because a steady state plasma concentration of endoxifen and its half-life was achieved throughout the treatment according to the embodiments described herein.