As part of his cocktail my husband has been taking 1mg of Alafacalcidol (vitamin D3) for almost two months now. Now I am not sure if this is the right dosage? It comes in capsules of 0.25mcg.
I think you meant to write 1 mcg alfacalcidol (rather than 1 mg). In the French study from 2001, the dose was 0.04 mcg/kg per day. For a man weighing 65 kg, that would work out to 2.6 mcg per day. I think you could go up to 2 mcg per day at least, but bloodwork should include testing for hypercalcemia.
In the GBM study using the 0.04 mcg/kg dose, there was no evidence of hypercalcemia in any of the patients after months of use.
Thank you Stephen, and yes, I meant 1mcg! Sorry. Actually I think I have already looked at this study previously and came up with 3.6mcg for my husband. This sounded a lot to me, but I think we will go up since there was no evidence of hypercalcemia...
One advantage of alfacalcidol (which is a calcitriol prodrug) over vitamin D3 is that it doesn't require activation by the kidneys - it is converted into calcitriol directly by the liver. This means alfacalcidol is useful even for people with reduced kidney function.
Granted, the indicated use of alfacalcidol in Canada is "management of hypocalcemia, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure" so using it for patients with normal renal function would be an off-label use.
A new article about vitamin D: 2018 https://www.ncbi.nlm.nih.gov/pubmed/29575677 "The active form of vitamin D (1α,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor. Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G."
My mom takes 4 months every day 2mkg (0.04mkg / kg) of alfacalcidol. A few days ago, we first made a blood test for the content of 25-hydroxycalciferol - an indicator of the vitamin D content in the body. Surprisingly, we got the value of 25-hydroxycalciferol in the blood within the norm - 61.38 ng / ml. I expected more. (Less than 30.00 ng / ml - vitamin D deficiency. More than 100.00 ng / ml - toxic concentration of vitamin D) Indicators of calcium, phosphorus, magnesium in the blood - normal.
Given some reports of the possible benefits of vitamin D in glioblastomas, my question and idea is to do a blood test for vitamin D and regulate the amount of alfacalcidol taken to approach the maximum, but non-toxic values. Your opinion?
Did she have 25-hydroxycholecalciferol in the blood measured at baseline, prior to starting the alfacalcidol? It would be useful to know whether her levels have been increasing over the past four months, or whether they have been stable over that time.
61.38 ng/mL = 153 nanomoles/liter (nanomolar). Unit convertor here: http://www.endmemo.com/medical/unitconvert/Vitamin__D.php
"sunshine alone can bring 25(OH)D concentrations to 210 nmol/L in normal people" [84 ng/mL].
It is difficult to get levels higher than this with sunshine alone, so apparently the body naturally wants to restrict levels from going much higher than that. You could potentially increase alfacalcidol dose by small steps until you achieve the target value.
information from: https://www.ncbi.nlm.nih.gov/pubmed/10232622
"As shown for numerous normal and cancer cell lines, calcitriol is at high concentrations an antiproliferative and prodifferentiating agent that induces apoptosis and inhibits cell migration (8). The antiproliferative properties of calcitriol, as described above, were also shown for central nervous system tumors, including glioblastoma cell lines (9). Beneficial effects of the vitamin D3 metabolite 1α- hydroxyvitamin D3 have been reported for the treatment of glioblastoma multiforme in a small phase II clinical study (10)."
So I'm thinking now about replacing alfacalcidol with calcitriol (https://www.drugs.com/mtm/calcitriol.html), which gives a higher level of 1α, 25-dihydroxyvitamin D3 (calcitriol) in the blood. By the way, the risk of hypercalcemia is higher. But this problem is solved by a weekly blood test for calcium and phosphate.
The question is a dose of calcitriol, which is significantly stronger than alfacalcidol.
In this study https://clinicaltrials.gov/ct2/show/NCT01293682 for breast cancer, a mega dose of calcitriol is used - 45 mg once a week for 12 weeks. Medication name: Rocatrol
"Participants assigned to one of the calcitriol arms took 45 micrograms (mcg) of calcitriol once weekly. This dose was selected based on previous research that showed reduced hypercalcemia by using a weekly dosing strategy [5, 6, 8]. Participants were advised to increase their water intake by 3–4 cups on the day they took the calcitriol and on the following Support Care Cancer day. Because a 45-mcg dose of calcitriol was not commercially available, bulk calcitriol was purchased from ChromaDex (Irvine, CA)..."
https://www.ncbi.nlm.nih.gov/pubmed/17066293 "DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer... Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients."
Alfacalcidol is a prodrug for calcitriol, and is rapidly converted to calcitriol in the liver. I've actually seen studies where taking alfacalcidol produced higher blood levels of calcitriol than taking calcitriol itself (both were taken orally if I recall correctly).
It is strange, but I can not find any studies on the effect of doses of alfacalcidol on calcitriol levels. Although I'm already looking for this week!) Conversely, these studies report that there is no increase in the levels of 25 OH D3 (calcidol) and 1a, 25 (OH) 2D3 (calcitriol) after the administration of alfacalcidol! http://sci-hub.tw/https://doi.org/10.1055/s-0042-103932 https://academic.oup.com/ndt/article/19/4/870/1810359
At clinicaltrials.gov, I see active trials in cancer with calcitriol, but not with alfacalcidol. Perhaps, since 2001, when alfacalcidol was tested for glioblastoma, did the paradigm change?
Synthetic calcitriol "Rocaltrol" is on sale. 1 capsule - 0.25 mkg. However, in these studies, mega-doses are used! https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749360/table/T2/?report=objectonly Thus, mega-doses of Rocaltrol can give completely different levels of calcitriol than 2-2.5 μg of alfacalcidol in studies of 2001 with glioblastoma.
Interesting Facts: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749360/ "...the inhibition of CYP3A4 may lead to reduced ability of the enzyme to oxidize calcitriol in the liver and thus sparing calcitriol catabolism to yield higher intracellular levels. Therefore, the metabolism of calcitriol in the intestine and liver could contribute more to calcitriol bioavailability and tissue levels than CYP24A189. The combination of calcitriol with CYP3A4 inhibitors, therefore, could allow for the use of lower doses of calcitriol and still achieve significant anticancer effects... ...Calcitriol biosynthesis and metabolism pathways are catalyzed by multiple CYP enzymes. This provides the opportunity to the researchers and clinicians to either stimulate calcitriol biosynthesis or inhibit its metabolism in an organ-specific manner, leading to higher exposure to endogenous or exogenously administered calcitriol."
Vitamin D3 has to undergo an intermediate step, first to 25 OH D3 (calcidiol) and then to calcitriol. Alfacalcidol doesn't undergo that intermediate step, it is converted directly into calcitriol. So alfacalcidol wouldn't be expected to increase blood calcidiol concentrations, only calcitriol concentrations. If alfacalcidol didn't increase blood calcitriol, there would be no point taking it.
See Table 4 in this study: http://www.jptcp.com/articles/oral-calcitriol-versus-oral-alfacalcidol-for-the-treatment-of-secondary-hyperparathyroidism-in-patients-receiving-hemodialysis-a-r.pdf
Blood calcitriol was tested at 6 weeks following oral calcitriol versus oral alfacalcidol administration. Oral alfacalcidol was more effective at increasing plasma calcitriol levels than oral calcitriol, which is very interesting.
Alfacalcidol isn't approved for use in the USA, which might explain the relative rarity of clinical trials compared to calcitriol.
I presume by "mega dose" you're talking about the study that combined 0.5 microgram per kg Rocaltrol WEEKLY with docetaxel.
Keep in mind the 2001 GBM trial used 0.04 microgram/kg per DAY, so that would be 0.28 microgram/kg per WEEK.
The weekly dose of Rocaltrol was therefore about twice the weekly dose of alfacalcidol in the 2001 GBM trial. At least we know that the dose in the GBM trial didn't lead to any significant hypercalcemia. Monitoring the blood for signs of hypercalcemia may be required for any significantly high dose of alfacalcidol or calcitriol/Rocaltrol.
Stephen and Semyon... could you advise me on a Alfacalcidol + Vitamin D dose for my mum?
She weighs 87kg and I would like to give her half the dose in Alfacalcidol and half in Vitamin D because of the price. Can you please advise me on the dosage?
Paul, I'll share the Brain Tumor Library with you, so you can download the study on alfacalcidol for GBM. It's in folder 1 (Therapies - humans studies) -> Alfacalcidol.
Typically, 25-hydroxycholecalciferol (calcidiol) levels are measured in the blood as the main indicator of vitamin D status in the body. But since alfacalcidol is converted directly into calcitriol in the body (and doesn't have to undergo an intermediate step as 25-hydroxycholecalciferol), this method of monitoring vitamin D status isn't sufficient. As Semyon mentioned, in the trial (Trouillas, 2001) "A dose of 0.04 µg/kg/day of alfacalcidol was administered orally each day. Calcemia, phosphoremia and magnesemia were assayed every 2 months."
and "There was no significant hypercalcemia, at the dose proposed, so that no interruption of the drug was necessary. No toxicity was observed on hepatic enzymes during the years of treatment."
See also the Pharma and non-pharma list of drugs and supplements in folder 0 of the library, for more details pertaining to each one.
I've not seen any evidence to support use of vitamin D-like drugs in combination with radiation. It might have radioprotective effect on healthy tissue (and by extension on cancer cells undergoing radiation). In the absence of data I might hold off on high dose vitamin D3/alfacalcidol supplementation until after radiation. In the trial (Trouillas 2001) it was used either in combination with alklyating chemotherapy (fotemustine), or as a monotherapy following chemotherapy.
Thank you guys. Regarding EGCG during radiotherapy I'm finding relatively conflicting evidence:
https://www.ncbi.nlm.nih.gov/pubmed/21676444
"Radiotherapy is effective in inducing apoptosis in DU145 cells, but its effect was significantly reduced in the presence of EGCG, and this was associated with an increase in the induction of manganese superoxide dismutase."
https://www.ncbi.nlm.nih.gov/pubmed/22280355
"These results provide hitherto unreported evidence that EGCG potentiated efficacy of radiotherapy in breast cancer patients, and raise the possibility that this tea polyphenol has potential to be a therapeutic adjuvant against human metastatic breast cancer."
I think you meant to write 1 mcg alfacalcidol (rather than 1 mg). In the French study from 2001, the dose was 0.04 mcg/kg per day. For a man weighing 65 kg, that would work out to 2.6 mcg per day. I think you could go up to 2 mcg per day at least, but bloodwork should include testing for hypercalcemia.
ReplyDeleteIn the GBM study using the 0.04 mcg/kg dose, there was no evidence of hypercalcemia in any of the patients after months of use.
http://www.ncbi.nlm.nih.gov/pubmed/11349882
I'll upload a copy of this to the Library.
Thank you Stephen, and yes, I meant 1mcg! Sorry. Actually I think I have already looked at this study previously and came up with 3.6mcg for my husband. This sounded a lot to me, but I think we will go up since there was no evidence of hypercalcemia...
DeleteHopeST - Do you mind me asking where you get your alphacalcidol?
DeleteCan someone share with me a source for alphacalcidol?
DeleteThis is approved in Canada but not in the USA. You could get in through any number of Canadian pharmacies
Deletehttps://www.canadadrugs.com/products/one-alpha
https://www.universaldrugstore.com/medications/One+Alpha/0.25mcg
https://www.northdrugstore.com/buy-One-Alpha.html
but you'd likely need a prescription first.
Also one have to check renal function (estimated GFR using CKD-EPI with blood tests, and ultrasound)!
ReplyDeleteOne advantage of alfacalcidol (which is a calcitriol prodrug) over vitamin D3 is that it doesn't require activation by the kidneys - it is converted into calcitriol directly by the liver. This means alfacalcidol is useful even for people with reduced kidney function.
DeleteGranted, the indicated use of alfacalcidol in Canada is "management of hypocalcemia, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure" so using it for patients with normal renal function would be an off-label use.
DeleteA new article about vitamin D:
ReplyDelete2018 https://www.ncbi.nlm.nih.gov/pubmed/29575677
"The active form of vitamin D (1α,25-dihydroxyvitamin D) acts as a steroid hormone and binds to the vitamin D receptor.
Vitamin D has several functions in the body including effects on brain development, neuroprotection and immunological regulation. It has been shown that vitamin D has antiproliferative activities in different cancer cell lines. Tacalcitol and calcipotriol are synthetic analogues of 1α,25-dihydroxyvitamin D with reduced effect on calcium metabolism. The aim of this study was to analyse the effects of tacalcitol and calcipotriol on cell viability, proliferation and migration in the human glioblastoma cell line T98G."
My mom takes 4 months every day 2mkg (0.04mkg / kg) of alfacalcidol.
A few days ago, we first made a blood test for the content of 25-hydroxycalciferol - an indicator of the vitamin D content in the body. Surprisingly, we got the value of 25-hydroxycalciferol in the blood within the norm - 61.38 ng / ml. I expected more.
(Less than 30.00 ng / ml - vitamin D deficiency. More than 100.00 ng / ml - toxic concentration of vitamin D)
Indicators of calcium, phosphorus, magnesium in the blood - normal.
Given some reports of the possible benefits of vitamin D in glioblastomas, my question and idea is to do a blood test for vitamin D and regulate the amount of alfacalcidol taken to approach the maximum, but non-toxic values. Your opinion?
Did she have 25-hydroxycholecalciferol in the blood measured at baseline, prior to starting the alfacalcidol? It would be useful to know whether her levels have been increasing over the past four months, or whether they have been stable over that time.
Delete61.38 ng/mL = 153 nanomoles/liter (nanomolar). Unit convertor here: http://www.endmemo.com/medical/unitconvert/Vitamin__D.php
"sunshine alone can bring 25(OH)D concentrations to
210 nmol/L in normal people" [84 ng/mL].
It is difficult to get levels higher than this with sunshine alone, so apparently the body naturally wants to restrict levels from going much higher than that. You could potentially increase alfacalcidol dose by small steps until you achieve the target value.
information from: https://www.ncbi.nlm.nih.gov/pubmed/10232622
Unfortunately, I find out all too late and the level of 25-hydroxycalciferol has never been measured before.
Deletehttp://sci-hub.tw/https://doi.org/10.1158/1078-0432.CCR-04-1968
ReplyDelete"As shown for numerous normal and cancer cell lines, calcitriol is at high concentrations an antiproliferative and prodifferentiating agent that induces apoptosis and inhibits cell migration (8). The antiproliferative properties of calcitriol, as described above, were also shown for central nervous system tumors, including glioblastoma cell lines (9). Beneficial effects of the vitamin D3 metabolite 1α- hydroxyvitamin D3 have been reported for the treatment of glioblastoma multiforme in a small phase II clinical study (10)."
So I'm thinking now about replacing alfacalcidol with calcitriol (https://www.drugs.com/mtm/calcitriol.html), which gives a higher level of 1α, 25-dihydroxyvitamin D3 (calcitriol) in the blood.
By the way, the risk of hypercalcemia is higher. But this problem is solved by a weekly blood test for calcium and phosphate.
The question is a dose of calcitriol, which is significantly stronger than alfacalcidol.
In this study https://clinicaltrials.gov/ct2/show/NCT01293682 for breast cancer, a mega dose of calcitriol is used - 45 mg once a week for 12 weeks.
DeleteMedication name: Rocatrol
http://sci-hub.tw/https://doi.org/10.1007/s00520-018-4094-4
Delete"Participants assigned to one of the calcitriol arms took 45 micrograms (mcg) of calcitriol once weekly. This dose was selected based on previous research that showed reduced hypercalcemia by using a weekly dosing strategy [5, 6, 8].
Participants were advised to increase their water intake by 3–4 cups on the day they took the calcitriol and on the following Support Care Cancer day. Because a 45-mcg dose of calcitriol was not commercially
available, bulk calcitriol was purchased from ChromaDex (Irvine, CA)..."
https://www.ncbi.nlm.nih.gov/pubmed/17066293
"DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer...
Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients."
Calcitriol is 1,25-dihydroxycholecalciferol
DeleteAlfacalcidol is 1-hydroxycholecalciferol
Alfacalcidol is a prodrug for calcitriol, and is rapidly converted to calcitriol in the liver. I've actually seen studies where taking alfacalcidol produced higher blood levels of calcitriol than taking calcitriol itself (both were taken orally if I recall correctly).
It is strange, but I can not find any studies on the effect of doses of alfacalcidol on calcitriol levels. Although I'm already looking for this week!)
DeleteConversely, these studies report that there is no increase in the levels of 25 OH D3 (calcidol) and 1a, 25 (OH) 2D3 (calcitriol) after the administration of alfacalcidol!
http://sci-hub.tw/https://doi.org/10.1055/s-0042-103932
https://academic.oup.com/ndt/article/19/4/870/1810359
At clinicaltrials.gov, I see active trials in cancer with calcitriol, but not with alfacalcidol.
Perhaps, since 2001, when alfacalcidol was tested for glioblastoma, did the paradigm change?
Synthetic calcitriol "Rocaltrol" is on sale. 1 capsule - 0.25 mkg. However, in these studies, mega-doses are used!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749360/table/T2/?report=objectonly
Thus, mega-doses of Rocaltrol can give completely different levels of calcitriol than 2-2.5 μg of alfacalcidol in studies of 2001 with glioblastoma.
Interesting Facts:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4749360/
"...the inhibition of CYP3A4 may lead to reduced ability of the enzyme to oxidize calcitriol in the liver and thus sparing calcitriol catabolism to yield higher intracellular levels. Therefore, the metabolism of calcitriol in the intestine and liver could contribute more to calcitriol bioavailability and tissue levels than CYP24A189. The combination of calcitriol with CYP3A4 inhibitors, therefore, could allow for the use of lower doses of calcitriol and still achieve significant anticancer effects...
...Calcitriol biosynthesis and metabolism pathways are catalyzed by multiple CYP enzymes. This provides the opportunity to the researchers and clinicians to either stimulate calcitriol biosynthesis or inhibit its metabolism in an organ-specific manner, leading to higher exposure to endogenous or exogenously administered calcitriol."
Vitamin D3 has to undergo an intermediate step, first to 25 OH D3 (calcidiol) and then to calcitriol. Alfacalcidol doesn't undergo that intermediate step, it is converted directly into calcitriol. So alfacalcidol wouldn't be expected to increase blood calcidiol concentrations, only calcitriol concentrations. If alfacalcidol didn't increase blood calcitriol, there would be no point taking it.
DeleteSee Table 4 in this study:
Deletehttp://www.jptcp.com/articles/oral-calcitriol-versus-oral-alfacalcidol-for-the-treatment-of-secondary-hyperparathyroidism-in-patients-receiving-hemodialysis-a-r.pdf
Blood calcitriol was tested at 6 weeks following oral calcitriol versus oral alfacalcidol administration. Oral alfacalcidol was more effective at increasing plasma calcitriol levels than oral calcitriol, which is very interesting.
Alfacalcidol isn't approved for use in the USA, which might explain the relative rarity of clinical trials compared to calcitriol.
I presume by "mega dose" you're talking about the study that combined 0.5 microgram per kg Rocaltrol WEEKLY with docetaxel.
DeleteKeep in mind the 2001 GBM trial used 0.04 microgram/kg per DAY, so that would be 0.28 microgram/kg per WEEK.
The weekly dose of Rocaltrol was therefore about twice the weekly dose of alfacalcidol in the 2001 GBM trial. At least we know that the dose in the GBM trial didn't lead to any significant hypercalcemia. Monitoring the blood for signs of hypercalcemia may be required for any significantly high dose of alfacalcidol or calcitriol/Rocaltrol.
Stephen, thank you very much for the detailed explanations!
DeleteBy the way, as I understood, 45 mcg of calcitriol was an impulse dose for 1 day a week.
Stephen and Semyon... could you advise me on a Alfacalcidol + Vitamin D dose for my mum?
DeleteShe weighs 87kg and I would like to give her half the dose in Alfacalcidol and half in Vitamin D because of the price. Can you please advise me on the dosage?
And should she take it before/during/after radiation? Should we ease in to the full dose?
DeleteHello, Paul!
DeleteThe total dose of alfacalcidol according to the 2011 study will be:
0.04mkg * 87kg = 3.48mkg
Thus, 1/2 dose will be 1.74 mkg
To this dose, I think it's safe to add 7500-10000ME of Vitamin D3.
In this case, it is necessary to check the level in the blood of calcium, ionized ion, phosphorus.
I think, alfacalcidol and vitamin D3 can be taken at any time of treatment, including the time of radiation therapy.
Paul, I'll share the Brain Tumor Library with you, so you can download the study on alfacalcidol for GBM. It's in folder 1 (Therapies - humans studies) -> Alfacalcidol.
DeleteTypically, 25-hydroxycholecalciferol (calcidiol) levels are measured in the blood as the main indicator of vitamin D status in the body. But since alfacalcidol is converted directly into calcitriol in the body (and doesn't have to undergo an intermediate step as 25-hydroxycholecalciferol), this method of monitoring vitamin D status isn't sufficient. As Semyon mentioned, in the trial (Trouillas, 2001) "A dose of 0.04 µg/kg/day of alfacalcidol was administered orally each day. Calcemia, phosphoremia and
magnesemia were assayed every 2 months."
and
"There was no significant hypercalcemia, at
the dose proposed, so that no interruption of the drug
was necessary. No toxicity was observed on hepatic
enzymes during the years of treatment."
See also the Pharma and non-pharma list of drugs and supplements in folder 0 of the library, for more details pertaining to each one.
I've not seen any evidence to support use of vitamin D-like drugs in combination with radiation. It might have radioprotective effect on healthy tissue (and by extension on cancer cells undergoing radiation). In the absence of data I might hold off on high dose vitamin D3/alfacalcidol supplementation until after radiation. In the trial (Trouillas 2001) it was used either in combination with alklyating chemotherapy (fotemustine), or as a monotherapy following chemotherapy.
Thank you guys. Regarding EGCG during radiotherapy I'm finding relatively conflicting evidence:
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/21676444
"Radiotherapy is effective in inducing apoptosis in DU145 cells, but its effect was significantly reduced in the presence of EGCG, and this was associated with an increase in the induction of manganese superoxide dismutase."
https://www.ncbi.nlm.nih.gov/pubmed/22280355
"These results provide hitherto unreported evidence that EGCG potentiated efficacy of radiotherapy in breast cancer patients, and raise the possibility that this tea polyphenol has potential to be a therapeutic adjuvant against human metastatic breast cancer."
Not sure how to move forward...