JPWO2020068755A5 - - Google Patents

Claims (40)

A pharmaceutical composition for treating myeloproliferative diseases, comprising compound I or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient,
(i) administering the pharmaceutical composition to a patient in need of treatment;
(ii) monitoring said patient's thiamine level, wherein said patient's thiamine level is adjusted if said thiamine level is below a reference value; 2. The pharmaceutical composition of claim 1, wherein the patient's thiamine level is assessed by analyzing one or more biomarkers for thiamine deficiency. 3. The pharmaceutical composition of claim 2, wherein said biomarker for thiamine deficiency is serum thiamine level. 4. The pharmaceutical composition of claim 2 or claim 3, wherein the level of said biomarker after administration of Compound I is below said reference value. 5. The pharmaceutical composition of any one of claims 1-4, wherein the patient's thiamine level is adjusted by administering thiamine or a thiamine equivalent to the patient. A pharmaceutical composition for treating myelofibrosis, comprising compound I or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, and administering the pharmaceutical composition and thiamine or A pharmaceutical composition wherein a combination therapy comprising a thiamine equivalent is administered. A pharmaceutical composition for alleviating thiamine deficiency, comprising compound I or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, and administering the pharmaceutical composition to a patient at risk of developing thiamine deficiency. and wherein said patient is simultaneously exposed to thiamine or a thiamine equivalent. 8. The method of any one of claims 1-7, wherein the thiamine equivalent is thiamine pyrophosphate. A pharmaceutical composition for treating a patient, comprising Compound I or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient,
(i) administering the pharmaceutical composition to the patient;
(ii) analyzing the patient's thiamine level; and (iii) administering thiamine or a thiamine equivalent to the patient if the patient's thiamine level is less than or equal to about 30 nM/L. 10. The pharmaceutical composition of Claim 9, wherein thiamine is administered to said patient in an amount of about 100 mg per day. 11. The pharmaceutical composition of claim 10, wherein thiamine is administered orally. 10. The pharmaceutical composition of claim 9, wherein thiamine is administered to said patient in an amount of about 250 mg to about 500 mg. 13. The pharmaceutical composition of claim 12, wherein thiamine is administered to said patient in an amount of about 250 mg. 13. The pharmaceutical composition of claim 12, wherein thiamine is administered to said patient in an amount of about 500 mg. 15. The pharmaceutical composition of any one of claims 12-14, wherein thiamine is administered intravenously. Thiamin has the following schedule:
TID about 500 mg for 2 or 3 days,
About 250 mg to about 500 mg daily (QD) for 3-5 days and about 100 mg QD for 90 days
10. The pharmaceutical composition of claim 9, administered according to 10. The pharmaceutical composition of Claim 9, wherein said patient is administered a thiamine equivalent sufficient to deliver about 100 mg of thiamine per day. 18. The pharmaceutical composition of claim 17, wherein said thiamine equivalent is administered orally. 10. The pharmaceutical composition of claim 9, wherein said patient is administered a thiamine equivalent sufficient to deliver from about 250 mg to about 500 mg of thiamine. 20. The pharmaceutical composition of Claim 19, wherein said thiamine equivalent is sufficient to deliver about 250 mg of thiamine. 20. The pharmaceutical composition of Claim 19, wherein said thiamine equivalent is sufficient to deliver about 500 mg of thiamine. 22. The pharmaceutical composition of any one of claims 19-21, wherein the thiamine equivalent is administered intravenously. The thiamine equivalent is according to the following schedule:
TID about 500 mg for 2 or 3 days,
About 250 mg to about 500 mg daily (QD) for 3-5 days and about 100 mg QD for 90 days
18. The pharmaceutical composition of claim 17, which is sufficient to deliver an amount of thiamine according to 24. The pharmaceutical composition of any one of claims 1-23, further comprising increasing magnesium levels in the patient. 25. The pharmaceutical composition of any one of claims 1-24, wherein the patient is suffering from a myeloproliferative disorder. 26. The pharmaceutical composition of claim 25, wherein said myeloproliferative disorder is myelofibrosis. 27. The pharmaceutical composition of claim 26, wherein said myelofibrosis is primary myelofibrosis. 28. The pharmaceutical composition of claim 27, wherein said primary myelofibrosis is selected from intermediate risk primary myelofibrosis and high risk primary myelofibrosis. 27. The pharmaceutical composition of claim 26, wherein said myelofibrosis is secondary myelofibrosis. 27. The pharmaceutical composition of claim 26, wherein the myelofibrosis is post-essential thrombocythemia myelofibrosis. 27. The pharmaceutical composition of claim 26, wherein the myelofibrosis is postpolycythemia vera myelofibrosis. 26. The pharmaceutical composition of claim 25, wherein said myeloproliferative disease is acute myelogenous leukemia (AML). 26. The pharmaceutical composition of claim 25, wherein said myeloproliferative disorder is polycythemia vera. 26. The pharmaceutical composition of claim 25, wherein said myeloproliferative disorder is essential thrombocythemia. A pharmaceutical composition for treating a patient, comprising Compound I or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient,
(i) administering said pharmaceutical composition ; and (ii) performing a cognitive assessment . 36. The pharmaceutical composition of Claim 35, wherein said evaluation is performed during the second 28-day cycle of Compound I administration. 36. The pharmaceutical composition of Claim 35, wherein said evaluation is performed during the third 28-day cycle of Compound I administration. 36. The pharmaceutical composition of Claim 35, wherein said evaluation is performed during every third cycle of at least three 28-day cycles of Compound I administration. 36. The pharmaceutical composition of Claim 35, wherein said assessment comprises a Mini-Mental State Examination. 36. The pharmaceutical composition of claim 35, further comprising analyzing the patient's thiamine level.