NZ728823B2 - Adjunctive therapy with 25-hydroxyvitamin d - Google Patents
Adjunctive therapy with 25-hydroxyvitamin dInfo
- Publication number
- NZ728823B2 NZ728823B2 NZ728823A NZ72882315A NZ728823B2 NZ 728823 B2 NZ728823 B2 NZ 728823B2 NZ 728823 A NZ728823 A NZ 728823A NZ 72882315 A NZ72882315 A NZ 72882315A NZ 728823 B2 NZ728823 B2 NZ 728823B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- hydroxyvitamin
- patient
- agent
- cancer
- hypocalcemia
- Prior art date
Links
- 235000021318 Calcifediol Nutrition 0.000 title claims abstract 44
- JWUBBDSIWDLEOM-XHQRYOPUSA-N (3e)-3-[(2e)-2-[1-(6-hydroxy-6-methylheptan-2-yl)-7a-methyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol Chemical compound C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2\C1=C\C=C1/CC(O)CCC1=C JWUBBDSIWDLEOM-XHQRYOPUSA-N 0.000 title claims abstract 33
- 238000011360 adjunctive therapy Methods 0.000 title claims abstract 4
- 239000003795 chemical substances by application Substances 0.000 claims abstract 27
- 208000013038 Hypocalcemia Diseases 0.000 claims abstract 20
- 230000000705 hypocalcaemia Effects 0.000 claims abstract 20
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- 238000009472 formulation Methods 0.000 claims 13
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- JWUBBDSIWDLEOM-NQZHSCJISA-N 25-hydroxy-3 epi cholecalciferol Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=CC=C1C[C@H](O)CCC1=C JWUBBDSIWDLEOM-NQZHSCJISA-N 0.000 claims 7
- KJKIIUAXZGLUND-ICCVIKJNSA-N 25-hydroxyvitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C KJKIIUAXZGLUND-ICCVIKJNSA-N 0.000 claims 7
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Abstract
Methods, compositions, and kits for adjunctive therapy using a modified release form of 25-hydroxyvitamin D are disclosed. The 25-hydroxyvitamin D may be administered with an agent that increases the risk of hypocalcemia and/or an anticancer agent. The adjunctive therapy is effective to treat and prevent iatrogenic hypocalcemia and/or secondary hyperparathyroidism, as well as delay cancer progression and the time to a post-treatment skeletal related event.
Claims (43)
1. Use of a 25-hydroxyvitamin D compound in the manufacture of a medicament for: i. treating or preventing iatrogenic hypocalcemia and secondary hyperparathyroidism in a patient treated with an agent that increases the risk of hypocalcemia; or ii. increasing bone mineral density in a patient treated with an agent that increases the risk of hypocalcemia; or iii. decreasing the blood level of a bone resorption marker in a patient treated with an agent that increases the risk of hypocalcemia; or iv. treating bone pain in a patient treated with an agent that increases the risk of hypocalcemia; or v. increasing the time to the first post-treatment skeletal-related event in a patient treated with an agent that increases the risk of hypocalcemia; or vi. restoring and maintaining blood 25-hydroxyvitamin D levels to at least 30 ng/mL, in a patient treated with an agent that increases the risk of hypocalcemia, wherein the 25-hydroxyvitamin D compound is in a modified release formulation and the 25- hydroxyvitamin D is selected from the group consisting of 25-hydroxyvitamin D2, 25- hydroxyvitamin D3, 25-hydroxyvitamin D4, 25-hydroxyvitamin D5, 25-hydroxyvitamin D7 and combinations thereof.
2. The use of claim 1, wherein the patient treated with an agent that increases the risk of hypocalcemia is receiving or has previously received treatment with an agent that increases the risk of hypocalcemia.
3. The use of claim 1 or claim 2, wherein the agent that increases the risk of hypocalcemia is selected from the group consisting of antiresorptive agents, anticonvulsant agents, corticosteroids, antihypercalcemia agents, antimicrobial agents, and combinations thereof. 46
4. The use of any one of the preceding claims, wherein the agent that increases the risk of hypocalcemia is an antihypercalcemia agent, optionally the anti-hypercalcemia agent comprises cinacalcet.
5. The use of claim 3 or 4, wherein the 25-hydroxyvitamin D is to be administered following administration of the antihypercalcemia agent.
6. The use of any one of claims 1-3, wherein the agent that increases the risk of hypocalcemia is an antiresorptive agent.
7. Use of a 25-hydroxyvitamin D compound in the manufacture of a medicament for: i. lowering elevated serum parathyroid hormone levels in a patient having a bone metastasis and being treated with an antiresorptive agent, where the patient is to be administered with an effective amount of said 25-hydroxyvitamin D; or ii. stabilizing serum calcium levels in a patient having a bone metastasis and being treated with an antiresorptive agent, wherein the 25-hydroxyvitamin D compound is in a modified release formulation and the 25- hydroxyvitamin D is selected from the group consisting of 25-hydroxyvitamin D2, 25- hydroxyvitamin D3, 25-hydroxyvitamin D4, 25-hydroxyvitamin D5, 25-hydroxyvitamin D7 and combinations thereof.
8. The use of claim 7, wherein the antiresorptive agent is selected from the group consisting of bisphosphonates, selective estrogen receptor modulators, calcitonin, hormones, monoclonal antibodies, and combinations thereof.
9. The use of any one of claims 6-8, wherein the antiresorptive agent comprises a RANKL inhibitor, optionally the RANKL inhibitor denosumab.
10. The use of any one of claims 6-8, wherein the antiresorptive agent comprises a bisphosphonate, optionally the bisphosphonate zoledronic acid.
11. Use of a 25-hydroxyvitamin D compound in the manufacture of a medicament for treating hungry bone syndrome in a patient in need thereof, wherein the 25-hydroxyvitamin D 47 compound is in a modified release formulation and the 25-hydroxyvitamin D is selected from the group consisting of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 25-hydroxyvitamin D4, 25-hydroxyvitamin D5, 25-hydroxyvitamin D7 and combinations thereof.
12. The use of any one of the preceding claims, wherein the patient has osteoporosis.
13. The use of any one of the preceding claims, wherein the patient has cancer.
14. Use of a 25-hydroxyvitamin D compound in the manufacture of a medicament for: i. managing iatrogenic hypocalcemia and secondary hyperparathyroidism in a patient with a bone metastasis receiving therapy with an antiresorptive agent, wherein the medicament prevents or reverses iatrogenic hypocalcemia and lowers the patient’s serum parathyroid hormone level; or ii. inhibiting the proliferation and migration of cancer cells; or iii. mitigating the progression of cancer in the bone; or iv. treating a patient having cancer and a bone metastasis, where treatment comprises the administration of (a) a prophylactic and continuing course of an effective amount of said 25-hydroxyvitamin D to stabilize serum 25-hydroxyvitamin D levels and calcium levels in said patient without causing or exacerbating hypercalcemia, followed by (b) treatment with an agent known to increase the risk of iatrogenic hypocalcemia, wherein the treatment in step (a) prevents and/or treats said iatrogenic hypocalcemia in said patient; or v. treating cancer in a patient, or vi. mitigating cancer progression and/or a skeletal related event in a patient with a bone metastasis from a solid tumor, where treatment comprises administration to said patient of (a) an anticancer agent; (b) an antiresorptive agent and (c) said 25-hydroxyvitamin D compound, wherein the combination of (a), (b), and (c) is effective to slow tumor growth and/or metastasis and increase the time to the first post-treatment skeletal-related event, wherein the 25-hydroxyvitamin D compound is in a modified release formulation and the 25- hydroxyvitamin D is selected from the group consisting of 25-hydroxyvitamin D2, 25- 48 hydroxyvitamin D3, 25-hydroxyvitamin D4, 25-hydroxyvitamin D5, 25-hydroxyvitamin D7 and combinations thereof.
15. The use of claim 14, option v or vi, wherein the anticancer agent is selected from the group consisting of azacitidine, axathioprine, bevacizumab, bleomycin, capecitabine, carboplatin, chlorabucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fluorouracil, gemcitabine, herceptin, idarubicin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, tafluposide, teniposide, tioguanine, retinoic acid, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, receptor tyrosine kinase inhibitors, and combinations thereof.
16. The use of claim 13-15, wherein the cancer is selected from the group consisting of bone cancer, bladder cancer, breast cancer, colon cancer, endometrial cancer, kidney cancer, leukemia, lung cancer, lymphoma, pancreatic cancer, prostate cancer, skin cancer, thyroid cancer, and metastatic forms thereof.
17. The use of any one of the preceding claims, wherein the patient has a metastatic bone cancer, metastatic prostate cancer, metastatic lung cancer, and/or metastatic breast cancer.
18. The use of any one of the preceding claims, wherein the patient has a bone tumor, optionally a bone metastasis from a solid tumor.
19. The use of any one of the preceding claims, wherein the patient has impaired renal function, optionally associated with Chronic Kidney Disease Stage 1, 2, 3, 4, or 5.
20. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to restore or maintain the patient’s serum calcium level to at least about 8.0 mg/dL, optionally in a range of about 8.3 mg/dL to about 11.6 mg/dL.
21. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to safely increase the patient’s serum level of 25-hydroxyvitamin D to at least 30 ng/mL, optionally in a range of about 30 ng/mL to about 100 ng/mL. 49
22. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to decrease the patient’s serum parathyroid hormone level, optionally by 30% or more.
23. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to decrease the patient’s serum parathyroid hormone related peptide levels.
24. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to safely increase the patient’s serum level of 1,25- dihydroxyvitamin D to above the normal range, optionally at least to 50 pg/mL.
25. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to achieve or maintain safe serum phosphorus levels and treat or prevent hypophosphatemia.
26. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to have a positive effect on the patient’s serum level of a marker of bone formation by more than what is accomplished with treatment with the antiresorptive agent alone.
27. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to decrease the patient’s serum level of a marker of bone resorption, optionally by at least 20%.
28. The use of claim 27, wherein the marker of bone resorption is selected from the group consisting of PTHrP, FGF23, NTX, CTX, TRAC-5b, and combinations thereof.
29. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to maintain or decrease the patient’s tumor burden.
30. The use of claim 29, wherein the effective amount of 25-hydroxyvitamin D is effective to maintain or decrease the patient’s serum level of a marker of tumor burden. 50
31. The use of claim 30, wherein the marker of tumor burden is selected from the group consisting of CEA, CA 125, CA15-3, CA 27-29, prostate specific antigen (PSA), and combinations thereof.
32. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is effective to inhibit the proliferation and/or migration of cancer cells.
33. The use of any one of the preceding claims, wherein the modified release formulation is selected from the group consisting of a sustained release formulation, a delayed release formulation, and a delayed, sustained release formulation.
34. The use of claim 32 or 33, wherein the modified release formulation comprises a waxy formulation.
35. The use of any one of claims 32-34 wherein the modified release formulation consists essentially of about 20 wt% paraffin, about 20 wt% to about 25 wt% glycerol monostearate, about 10 wt% a mixture of lauroyl macrogolglycerides and lauroyl polyoxylglycerides, about 30 wt% to about 35 wt% mineral oil, and about 10 wt% to about 15 wt% hydroxyl propyl methylcellulose.
36. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is to be administered in an oral sustained release formulation.
37. The use of any one of the preceding claims, wherein the 25-hydroxyvitamin D is to be administered in the form of a capsule.
38. The use of any one of the preceding claims, wherein the effective amount of 25- hydroxyvitamin D is absorbed primarily in the ileum and/or colon of the patient.
39. The use of any one of the preceding claims, wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D3 and/or 25-hydroxyvitamin D2.
40. The use of any one of the preceding claims, wherein the 25-hydroxyvitamin D comprises 25-hydroxyvitamin D3. 51
41. The use of any of the preceding claims, wherein the 25-hydroxyvitamin D is to be administered in a dosage of 30 µg to 300 µg per day.
42. Use of a 25-hydroxyvitamin D compound in the manufacture of a modified release formulation for adjunctive therapy to treat or prevent hypocalcemia in a patient in need thereof, wherein the 25-hydroxyvitamin D is selected from the group consisting of 25- hydroxyvitamin D2, 25-hydroxyvitamin D3, 25-hydroxyvitamin D4, 25-hydroxyvitamin D5, 25- hydroxyvitamin D7 and combinations thereof.
43. A pharmaceutical composition comprising (a) a 25-hydroxyvitamin D compound and (b) an agent that increases the risk of hypocalcemia and/or an anticancer agent, wherein the 25-hydroxyvitamin D compound is in a modified release form and the 25-hydroxyvitamin D is selected from the group consisting of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3, 25- hydroxyvitamin D4, 25-hydroxyvitamin D5, 25-hydroxyvitamin D7 and combinations thereof.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462034604P | 2014-08-07 | 2014-08-07 | |
PCT/EP2015/068219 WO2016020508A2 (en) | 2014-08-07 | 2015-08-06 | Adjunctive therapy with 25-hydroxyvitamin d |
Publications (2)
Publication Number | Publication Date |
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NZ728823A NZ728823A (en) | 2024-01-26 |
NZ728823B2 true NZ728823B2 (en) | 2024-04-30 |
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