25-HYDROXYVITAMIN D2 AND/OR D3 FOR USE IN OBESITY
20230248744 · 2023-08-10
Assignee
Inventors
Cpc classification
A61K31/59
HUMAN NECESSITIES
A61K31/592
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K31/593
HUMAN NECESSITIES
A61K31/592
HUMAN NECESSITIES
A61K31/593
HUMAN NECESSITIES
International classification
A61K31/592
HUMAN NECESSITIES
A61K31/593
HUMAN NECESSITIES
Abstract
The present invention relates to the field of vitamin D insufficiency and deficiency, viz. too low blood levels of 25(OH)D, and to their prevention and treatment. It provides a vitamin D supplement which comprises (i) a combination of 25(OH)D3 and/or 25(OH)D2 and vitamin D2; or (ii) a combination of 25(OH)D3 and/or 25(OH)D2 and vitamin D3; or (iii) a combination of 25(OH)D3 and/or 25(OH)D2 and a combination of vitamin D2 and vitamin D3, for use in the treatment of and/or prophylaxis of vitamin D insufficiency or deficiency in obese persons, overweight persons having the tendency to get obese or persons having a history of malabsorption of vitamin D or persons with a genetic disposition to develop obesity. Also provided are corresponding compositions and dosage regimens comprising such vitamin D supplements as well as kits comprising such compositions. Furthermore, corresponding dosage regimens for daily administration and corresponding product package inserts are also provided. The invention also relates to corresponding methods of treatment.
Claims
1. A composition comprising a vitamin D supplement for use in the treatment of and/or prophylaxis of vitamin D insufficiency or deficiency in obese persons, wherein the composition comprises a unit dose of vitamin D and 25(OH)D in a dosage for daily administration selected from the group as follows: (i) for individuals of BMI of 30 to 36 of unknown or unreliably known level of 25(OH)D in blood, respectively, who have a normal lifestyle with respect to UV-light exposure and daily uptake of vitamin D, the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts at the lower end of the range of 5 to 7.5 μg of each of the vitamin D and the 25(OH)D, wherein the lower end of the range means to encompass the range from the lowest end of the range up to the middle of the specified range; (ii) for individuals of BMI of 30 to 36 of unknown or unreliably known level of 25(OH)D in blood, respectively, who have an unfavorable lifestyle with respect to UV-light exposure and daily uptake of vitamin D, the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts at the higher end of the range of 5 to 7.5 μg of each of the vitamin D and the 25(OH)D, wherein the higher end of the range means to encompass the range from the middle of the range up to the highest end of the specified range; (iii) for individuals of BMI of 30 to 36 of reliably known level of 25(OH)D in blood of >20 to 30 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts in the range of 5 to 7.5 μg of each of the vitamin D and the 25(OH)D; (iv) for individuals of BMI of 30 to 36 of reliably known level of 25(OH)D in blood of >10 to 20 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1.5, with the dose of vitamin D at 5 to 7.5 μg and the dose of 25(OH)D at 7.5 to 11 μg; (v) for individuals of BMI of 30 to 36 of reliably known level of 25(OH)D in blood of ≤10 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 2, with the dose of vitamin D at 5 to 7.5 μg and the dose of 25(OH)D at 10 to 15 μg; (vi) for individuals of BMI of 37 to 43 of unknown or unreliably known level of 25(OH)D in the blood, respectively, who have a normal lifestyle with respect to UV-light exposure and daily uptake of vitamin D, the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts at the lower end of the range of 7.5 to 11 μg of each of the vitamin D and the 25(OH)D, wherein the lower end of the range means to encompass the range from the lowest end of the range up to the middle of the specified range; (vii) for individuals of BMI of 37 to 43 of unknown or unreliably known level of 25(OH)D in the blood, respectively, who have an unfavorable lifestyle with respect to UV-light exposure and daily uptake of vitamin D, the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts at the higher end of the range of 7.5 to 11 μg of each of vitamin D and the 25(OH)D, wherein the higher end of the range means to encompass the range from the middle of the range up to the highest end of the specified range; (viii) for individuals of BMI of 37 to 43 of reliably known level of 25(OH)D in blood of >20 to 30 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1.5 to 1, with the dose of vitamin D at 7.5 to 11 μg, and a dose of 25(OH)D of 5 to 7.5 μg; (ix) for individuals of BMI of 37 to 43 of reliably known level of 25(OH)D in blood of >10 to 20 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts of 7.5 to 11 μg of each of the two products; (x) for individuals of BMI of 37 to 43 of reliably known level of 25(OH)D in blood of ≤10 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1.5, with the dose of vitamin D at 7.5 to 11 μg, and a dose of 25(OH)D of 11 to 17 μg; (xi) for individuals of BMI of more than 43 of unknown or unreliably known level of 25(OH)D in blood, respectively, who have a normal lifestyle with respect to UV-light exposure and daily uptake of vitamin D, the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts at the lower end of the range of 11 to 15 μg of each of the two products, wherein the lower end of the range means to encompass the range from the lowest end of the range up to the middle of the specified range; (xii) for individuals of BMI of more than 43 of unknown or unreliably known level of 25(OH)D in blood, respectively, who have an unfavorable lifestyle with respect to UV-light exposure and daily uptake of vitamin D, the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts at the higher end of the range of 11 to 15 μg of each of the vitamin D and the 25(OH)D, wherein the higher end of the range means to encompass the range from the middle of the range up to the highest end of the specified range; (xiii) for individuals of BMI of more than 43 of reliably known level of 25(OH)D in blood of >20 to 30 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1.5 to 1, with the dose of vitamin D at 11 to 15 μg, and a dose of 25(OH)D of 7.5 to 10 μg; (xiv) for individuals of BMI of more than 43 of reliably known level of 25(OH)D in blood of >10 to 20 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts of 11 to 15 μg of each of the vitamin D and the 25(OH)D; or (xv) for individuals of BMI of more than 43 of reliably known level of 25(OH)D in blood of ≤10 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1.5, with the dose of vitamin D at 11 to 15 μg, and a dose of 25(OH)D of 17 to 22.5 μg.
2. The composition according to claim 1, wherein for individuals of BMI of 30 to 36 of reliably known level of 25(OH)D in blood of >20 to 30 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts in the range of 5 to 7.5 μg of each of the vitamin D and the 25(OH)D.
3. The composition according to claim 1, wherein for individuals of BMI of 30 to 36 of reliably known level of 25(OH)D in blood of >10 to 20 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1.5, with the dose of vitamin D at 5 to 7.5 μg and the dose of 25(OH)D at 7.5 to 11 μg.
4. The composition according to claim 1, wherein for individuals of BMI of 30 to 36 of reliably known level of 25(OH)D in blood of ≤10 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 2, with the dose of vitamin D at 5 to 7.5 μg the dose of 25(OH)D at 10 to 15 μg.
5. The composition according to claim 1, wherein for individuals of BMI of 37 to 43 of reliably known level of 25(OH)D in blood of >20 to 30 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1.5 to 1, with the dose of vitamin D at 7.5 to 11 μg, and a dose of 25(OH)D of 5 to 7.5 μg.
6. The composition according to claim 1, wherein for individuals of BMI of 37 to 43 of reliably known level of 25(OH)D in blood of >10 to 20 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts of 7.5 to 11 μg of each of the vitamin D and the 25(OH)D.
7. The composition according to claim 1, wherein for individuals of BMI of 37 to 43 of reliably known level of 25(OH)D in blood of ≤10 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1.5, with the dose of vitamin D at 7.5 to 11 μg, and a dose of 25(OH)D of 11 to 17 μg.
8. The composition according to claim 1, wherein for individuals of BMI of more than 43 of reliably known level of 25(OH)D in blood of >20 to 30 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1.5 to 1, with the dose of vitamin D at 11 to 15 μg, and a dose of 25(OH)D of 7.5 to 10 μg.
9. The composition according to claim 1, wherein for individuals of BMI of more than 43 of reliably known level of 25(OH)D in blood of >10 to 20 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1 and in amounts of 11 to 15 μg of each of the vitamin D and the 25(OH)D.
10. The composition according to claim 1, wherein for individuals of BMI of more than 43 of reliably known level of 25(OH)D in blood of ≤10 ng/mL the dose comprises vitamin D and 25(OH)D in a ratio of 1 to 1.5, with the dose of vitamin D at 11 to 15 μg, and a dose of 25(OH)D of 17 to 22.5 μg.
11. The composition according to claim 1, wherein 25(OH)D is 25(OH)D3 and vitamin D is vitamin D3.
Description
[0131] In the following the preferred methods and uses in accordance with the present invention are described. For an easier understanding it is referred to the figures which should not be construed as limiting the invention in any way.
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[0136]
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[0139]
[0145] Of course, the difference between calculated arrival and observed blood level describes just disappearance in the course of the uptake and the short subsequent phase. It does not per se distinguish disappearance due to deposition and other body functions such as, e.g., metabolism.
[0146]
[0147]
[0148]
[0149] *) The dose may be lowered further and/or vitamin D may be left out completely in case of an extreme favorable life style etc.
[0150] **) Move from F.1 to F.2, from F.5 to F.6, and from F.8 to F.9, repectively, if the person has a very unfavorable lifestyle etc. and is at the upper end of the respective BMI-range and is very tall.
[0151] ***) Dosages may be adapted beyond the respective range, in case of analytical results far outside of the ranges generally observed for the respective BMI-group. E.g., vitamin D may be raised beyond 15 μg in case of heavily inflammatory obesity.
[0152] If considering the experience, e.g., that subjects with a BMI of about 35 (viz. a BMI between 32.5 and 37.5) need in the average roughly 2 to 3 times higher supplementation of vitamin D than subjects with a BMI of about 25 (i.e a BMI between 22.5 and 27.5) and if using Table 2 to define corresponding “normal groups” (of US men) one finds the following weighed average weights: For the BMI 25 group 80.5 kg and for the BMI 35 group 107.5 kg. In other words: The weight-increase is 33.5%, and the BMI-increase is 40%. None of the two values “explains” the more than doubled vitamin D-demand, and therefore additional factors must be considered.
[0153] The van Groningen et al. publication cited above recommends administering the total “loading dose” over many weeks and underlines that the required dosage depends on the body weight (BW) which appears in the formula, but not the BMI—so that no correlation with the BMI was found. However, van Groningen et al. do not address the question whether and how the initial level of insufficiency or deficiency was correlated with the BMI. In addition, the publication explicitly excludes the application of the formula in case of obesity which is defined by van Groningen et al. as being a BW >120 kg (!).
[0154] It would be surprising, if obese individuals who easily absorb lipids from their guts had a diminished absorption of vitamin D, while it is conceivable that they have in the average a reduced 25-hydroxylation activity of their liver. Our observation that much less of the dosed vitamin D3 per se appears in the blood of obese people than in non-obese people may, therefore, have to be interpreted as follows: vitamin D3 enters the body mainly via the lymphatic pathway, and the part not appearing in the blood of obese is “lost” elsewhere, particularly in adipose tissue.
[0155] It is assumed in the following that about ⅔ of the vitamin D administered to normal individuals is rather rapidly forming 25(OH)D, while
[0156] The followed time/concentration-curves after administration to obese, normal, and malabsorptive individuals, respectively, of a single high oral dose of vitamin D3 (p.o.) as presented in the Examples part further below show distinctly differing overall shapes (see
[0160] In order to further analyze the results, the shape of the concentration/time-curves describing the observed average blood levels of vitamin D3 was used to approximately calculate its total uptake into blood after dosage. The calculation was based on the assumptions compiled in the comments regarding
[0161]
[0162] When comparing deposition in healthy obese and normal low BMI subjects, one finds [0163] at the time point of 15 hours 1.5 times more and [0164] at the time point of 24 hours 1.48 times more deposition in the healthy obese,
[0165] wherein the same correction regarding metabolism, as described above, was used for the obese and for the normal individuals, viz. 1.5 ng/mL at 15 hours and 3.5 ng/mL at 24 hours, respectively. These values come from
[0166] Thus, if assuming a total blood volume of 5 liters in both cases, the healthy obese subjects deposited in the first 24 hours 92.5 μg and the normal subjects 62.5 μg of vitamin D3. The following was considered in view of calculating the mean amounts of body fat of the two groups: The average BMI of the subjects, their average age (32+/−2.7 years) and their gender (8 females, 2 males). It was assumed that they have average height (1.7 m). The published formulae:
[0167] (https://www.calculator.net/body-fat-calculator.html—cp. P. Deurenbeg et al., Br. J. Nutr. 65(2), 105-14 (1991)) cited here was used to derive body fat percentages (BFP) from the BMIs:
[0168] Body Fat Percentage (BFP) Formula for Adult Males:
BFP=1.20×BMI+0.23×Age−16.2
[0169] Body Fat Percentage (BFP) Formula for Adult Females:
BFP=1.20×BMI+0.23×Age−5.4
[0170] These calculations yield the following results: [0171] for the normal BMI group BFP=26.92%, which results in 17.58 kg body fat, and [0172] for the healthy obese group BFP=37.48%, which results in 34.01 kg body fat.
[0173] The ratio “mass/mass” of body fat of the two groups is R.sub.M=1.935 and the ratio “surface/surface” of the body fat is R.sub.S=R.sub.M.sup.2/3=1.553 (assuming congruence, in particular similar distribution of sizes and dimensions of adipocytes), viz. close to the about 1.50 reported here for deposition. This may be interpreted that the given dose of vitamin D3 resulted after 24 hours in a comparable load of the relevant surfaces in and on adipocytes of our low and high BMI subjects. The present inventors have discovered this surprising relationship, which is important when defining upper limits for vitamin D per se and optimized combinations 25(OH)D plus vitamin D to be supplemented to individuals who are overweight or obese or have a tendency to get obese.
[0174] The two discussed curves in
[0175] Thereby this present discussion, the slow-down of metabolism in obesity (including 24-hydroxylation of 25(OH)D), the difference in blood volume, the in the average larger size of adipocytes and of lipid droplets in obesity, and the low BMI subjects' comparatively increased deposition in non-fatty tissues strongly suggest that the high and the low BMI subjects achieved similar density of vitamin D3 on the critical surfaces in fatty tissue.
[0176] The following relates to the coverage of the surface of adipocytes with vitamin D3. Referring to the publication by Karin G. Stenkula et al. (Am J Physiol Regul Integr Comp Physiol 315: R284-R295, 2018) on adipose cell size and reasonably considering the size-distribution reported there, the percentage of the relevant surfaces on and in adipocytes, which has been covered by no more than a mono-molecular layer of vitamin D as deposited in our low BMI group after 2% days, has been calculated. A homogenous cell diameter of 50 μm was determined to deliver about the same overall cell-surface one calculates by working with the rather wide experimental distribution of cell sizes as reported by Karin G. Stenkula et al. Thereby it was in the sense of a model consideration assumed that cubes containing large lipid droplet cubes can be used to describe the cells' shape (in other words: cubes of an edge-length of 50 μm enclosing cubes of about the same size were determined to represent a reasonable model for the description of the combined surface of the variable size cells' with their lipid droplets). In addition, it was assumed—in line with the observations reported in the already cited work of Susanne Prattes et al. (Journal of Cell Science 113, 2977-2989 (2000) https://jcs.biologists.org/content/joces/113/17/2977.full.pdf) that the critical surfaces consist in the external and the internal side of the cell membrane and the surface of the lipid droplets (all three assumed to have about the same size). Working with 17.6 kg of fatty tissue, with a deposition of approximatively 7400 I.U. of vitamin D3 after 2½ days, and with a surface of approximatively 2 nm.sup.2 covered by a single molecule of vitamin D3 resulted in about 0.01% surface coverage. The following can be concluded: On the one hand, it is not necessary to assume migration of vitamin D into lipid droplets to explain the observations made. On the other hand, the adipocytes' capacity to pick-up vitamin D without impacting its cellular physiology is not endless.
[0177] The lasting increase with regard to baseline by about 5 ng/mL of the blood level of 25(OH)D3 in low and high BMI subjects (
[0178] Administering a high dose of vitamin D3 led after 24 hours to a ratio R of about 1.5 times higher deposition in case of the higher BMI subjects. Thereby R is herein understood as the ratio of deposition between the higher BMI subjects and normal BMI subjects. Thus, the ratio R is approximately the amount of vitamin D (in the experimental case described herein D3) leaving the blood and being deposited in high BMI subjects divided by the amount of vitamin D leaving the blood and being deposited in low BMI subjects. In this connection the term “approximately” is used because the actual observable is the respective concentration of vitamin D present in blood at the beginning and the end of the period of observation. This means that metabolism is neglected (introducing a minor error, because deposition is in the discussed early phase much more important than metabolism and because the metabolic activity in high and low BMI subjects is rather similar). In addition, one has to consider the total blood volume (which is somewhat higher in the high BMI subjects) when calculating amounts on the basis of concentrations in the blood.
[0179] After 2½ days the relevant impact of deposition comes to an end. Deposition-dissolution-equilibria and metabolism take over. The ratio regarding total deposition in obese versus non-obese cannot anymore be reasonably approximated based on the approach used to determine the total uptake into blood for the initial phase of the concentration/time-curves. Working just with the difference to C.sub.max and considering the differing blood volumes results at this point in R=1.05 times higher deposition in fatty tissues in the high BMI case (again disregarding differences of metabolism, which play a minor role).
[0180] Just for the sake of clarity it is emphasized that non-identical ways were used to calculate the above two R values for 24 hours and for 2½ days, respectively.
[0181] Fatty tissues play the dominant role regarding vitamin D deposition, in particular in obese persons. To neglect deposition in other tissues would, however, be inaccurate, particularly when discussing the fate of 25(OH)D and 1,25(OH)D2. Deposition of 25(OH)D and 1,25(OH)D2 must be considered when interpreting the steady (viz. to be understood as constant) level of 25(OH)D3 as observed in our experiments for two weeks after administering vitamin D3. It must be considered as well when deciding to supplement vitamin D and 25(OH)D, viz. two related pro-hormones together, in carefully adjusted amounts. This combined dosage of vitamin D and 25(OH)D in specific amounts has now been found to be better than dosing larger amounts of vitamin D, in particular vitamin D3, to obese individuals, wherein vitamin D3 is loaded into adipocytes. According to the present inventors, the goal is to achieve a vitamin D surface density on the adipocytes of obese individual that matches the ideal surface density in normal, non-obese individuals.
[0182] According to the finding that the identical dose of vitamin D3 likely results in comparable vitamin D surface density in adipocytes of two (vitamin D3 insufficient or vitamin D3 deficient) groups of individuals differing by roughly 10 BMI-units, it can be considered unlikely that the R ratio as defined herein strongly changes with the dose of vitamin D, in particular when reducing the dose of vitamin D.
[0183] It is further stipulated that achieving the targeted optimum surface density of vitamin D in and on adipocytes of vitamin D insufficient or deficient obese individuals will generally not normalize their vitamin D status in terms of blood level of 25(OH)D. According to the present invention, this deficit is preferably compensated by supplementing 25(OH)D in addition.
[0184] The dose of 25(OH)D to be supplemented in addition to the adipose tissues' limited needs for vitamin D depends on the individual's level of insufficiency or deficiency and to an extent on the formulation of 25(OH)D employed. Further parameters which play a certain role regard, e.g., gender, age, and lifestyle (including diet). Thereby in particular the lifestyle impacts the level of insufficiency or deficiency, besides impacting obesity. There aren't many reliable studies considering these parameters and linking dosages of 25(OH)D with the vitamin D status achieved.
[0185] The following Table 3 summarizes optimized conceivable supplementation schemes according to the present invention for healthy obese individuals displaying frequently encountered levels of vitamin D insufficiency or deficiency. It differs from the prior art in particular with regard to the low dosages of vitamin D per se from what has up to today been broadly advocated or tolerated, respectively. It further departs from cautious vitamin D3 supplementation recommendations for vitamin D insufficient normal adults (BMI ≈25 kg/m.sup.2—normal supplementation p.o.=200-600 I.U./day). According to the present invention, depending, i.a., on the person's lifestyle, the dosages in the table may be supplemented throughout the year or just in the months of reduced sun-exposure. The daily doses shown may be translated to equivalent weekly dosage schemes. Table 3 disregards specific malabsorptive patients (e.g. after bariatric surgery). It is applicable for healthy obese as well as unhealthily obese individuals, in particular in connection with the footnotes accompanying the decision tree shown in
TABLE-US-00003 TABLE 3 Recommended daily administration of vitamin D supplements. Initial deficiency/insufficiency (25(OH)D in ng/mL of blood) Level of >20 to 30 >10 to 20 ≤10 obesity Contents Ratio Contents Ratio Contents Ratio (BMI) Components [μg] D/25(OH)D [μg] D/25(OH)D [μg] D/25(OH)D Slight Vit. D 5-7.5 1/1 5-7.5 1/1.5 .sup. 5-7.5 1/2 (30-36) 25(OH)D 5-7.5 (F.1) 7.5-11 (F.2) 10-15 (F.3) Clear Vit. D 7.5-11 1.5/1 7.5-11 1/1 7.5-11 1/1.5 (37-43) 25(OH)D 5-7.5 (F.4) 7.5-11 (F.5) 11-17 (F.6) Extreme Vit. D 11-15.sup. 1.5/1 11-15 1/1 11-15 1/1.5 (>43) 25(OH)D 7.5-11 (F.7) 11-15 (F.8) .sup. 17-22.5 (F.9)
[0186] Remarks: [0187] 15 μg vitamin D per day (=600 IU) is according to the current view of diverse medical societies a normal, non-elevated daily supplementation dose! [0188] In this table the calculated value of 11.25 has been rounded to 11. The findings summarized in Table 3 can be transformed into a flow chart which is provided herewith as
[0204] While there are indications in the flow chart (
[0205] The term “lower end of the range” as used herein is meant to encompass the range from the lowest end of the range up to the middle of the specified range.
[0206] The term “higher end of the range” as used herein is meant to encompass the range from the middle of the specified range up to the highest end of the range.
[0207] The term “normal lifestyle with respect to UV-light exposure” is meant to be a qualified estimation by a skilled person of the average amount of hours per day a patient is exposed to UV-radiation from natural sources (sunlight) and/or from UV-radiation lamps during a given period of time such as e.g. the last several weeks or the last few months. The UV light exposure can also be derived based on measurements by a small wearable device such as the one described in an article in ScienceDaily on Jan. 9, 2018 (see: Northwestern University. “World's smallest wearable device warns of UV exposure, enables precision phototherapy.” ScienceDaily. ScienceDaily, 6 Dec. 2018. <www.sciencedaly.com/releases/2018/12/181206114707.htm; last asessed Mar. 21, 2021).
[0208] As understood herein, 25(OH)D3 dosage may undergo adaptations based on analytical blood level determinations. The fields highlighted in bold in Table 3 address cases of obesity plus insufficiency/deficiency most likely encountered in modern civilizations. According to the present invention, the respective dosages and ratios may in healthy obese adults be applied without frequent measurements of the vitamin D status. According to the present invention, persons who are tall and obese (or heavy and obese) should preferably be dosed according to or go for the higher end, respectively, of the applicable ranges given in the table. The same holds for people at the more unfavorable end of the indicated ranges of insufficiency or deficiency, respectively. The lower end of the range in the table's upper left field is preferably also suitable for individuals who are non-obese, but overweight and borderline insufficient as well as individuals just having a tendency to get obese (e.g. based on genetics).
[0209] For the individuals with the highest BMI, the 25(OH)D3 dosages in the above Table 3 are cautiously increased by raising the dose and leaving the ratio unchanged, to ensure adequate, but non-exaggerated supplementation of adipocytes with vitamin D per se and to normalize the (blood level-based) vitamin D status with 25(OH)D. Considering that our experimental results showed no statistically significant BMI-dependence of the improvement as achieved by a given dose of 25(OH)D3, one might have expected no raising of its dose. There are several reasons for raising it anyway: We cannot absolutely exclude a slight trend towards lower levels achieved when dosing 25(OH)D to obese subjects. The total blood volume (BV) of a person of a given height is increasing with increasing BMI—proportional to its square root. Finally, there likely is a feedback control mechanism mitigating the release from adipocytes of vitamin D (and/or vitamin D metabolites), if the blood level of the metabolites gets higher.
[0210] Such a feedback control may be regarded as logical addition to the often-cited evolutionary role of the deposition of vitamin D in fatty tissues. It would have kept vitamin D3 levels in adipocytes high in summer when 25(OH)D3 blood levels were high and growth of fatty tissue was favorable, and it would have fostered vitamin D release and the burning of body fat when the sun was low and little vitamin D3 was formed. An argument in favor of the mentioned feedback control is, by the way, the less than additive increase of the 25(OH)D3 level caused by parallel administration of 25(OH)D3 and vitamin D3 (cp. the already mentioned article by Alexander Jetter et al., Bone 59, 14-19 (2014)). The main differences between the present invention and the study of Jetter et al. are that Jetter et al. does not address obesity and uses doses which differed from ours. Jetter's study supports the interpretation that the two, D3 and 25(OH)D3 go to different compartments without mutually influencing the initial distribution to a significant extent. The study can be interpreted in the sense that the clear effect upon the vitamin D status 25(OH)D3 has, is marginally affected, if at all, by the parallel administration of D3 and that there seemingly is a trend towards further weakening of the anyway weak effect D3 has upon the vitamin D status (viz. the 25(OH)D3 blood level), if it is dosed in parallel to 25(OH)D3.
[0211] Pointing in the same direction is the observation that a given dose of vitamin D raises a comparatively high baseline level of 25(OH)D to a weaker absolute extent than it raises a comparatively low baseline level of 25(OH)D (cp. Muhammad M. Hammami et al., BMC Endocr. Disord. 2017; 17: 12—https.//www.ncbi.nlm.nih.gov/pmc/articles/PMC5324269/). Assuming that this discussed feedback control exists leads to the conclusion that a relatively low (blood level-based) vitamin D status may be desirable, if the focus is on controlling obesity. However, the approach has to be kept within reasonable limits. Thus, more than 30 ng/mL of 25(OH)D may be targeted in cases of extreme obesity (which probably were never encountered in ancient times), in order to avoid unhealthy vitamin D depletion of adipocytes. In cases of moderate and healthy obesity, however, 30 ng/mL but not more may be regarded as reasonable compromise, unless there are other more relevant priorities, like, e.g., the stimulation of the immune system to mitigate the effect of viral infections.
[0212] The proposed vitamin D supplementation scheme of the present invention, according to Table 3, shall now be discussed in view of the whole population's distribution of heights and weights as visualized in Table 1 for American male adults. Looking at the extremes Table 1 covers (upper left and lower right fields) leads to factors of approximatively (≈) 1.33 for heights, ≈2.25 for BMIs, and ≈4 for weights. Using the respective cited formula further leads to factors of ≈11.8 for total body fat weight and (assuming congruence)≈5.2 for the body fat surface, which as discussed herein is expected to govern at least short-term deposition. As non-congruency will rather reduce than add to the surface factor, as deposition increases with increasing fatty tissue surface, and as a BMI of 20 does not have to be considered in the context of obesity, it can be estimated that the factor 3 separating the lowest and the highest vitamin D3 dose according to Table 3 is roughly what it takes to reasonably cover the adipocytes' respective needs in different healthy obese or potentially obese individuals.
[0213] The combination of 25(OH)D3 and vitamin D3 is the prototype of the present invention. However, as understood herein, it can employ the vitamin D per se and the 25-hydroxylated metabolite, respectively, it can be based on the D3- and/or the D2-series, and it can be based on all the conceivable combinations of those options. The considerations of ratio of 25(OH)D/vitamin D in this combination and the dosages can in terms of the basic concept presented be extrapolated to the other combinations of two corresponding components and to all the combinations of three or four components. The reason is the strong similarity of the two vitamins, on the one hand, and the analogous similarity of the two 25-hydroxylated metabolites, on the other hand. Of particular interest amongst the two component combinations is the one of 25(OH)D2+vitamin D2. It consists exclusively in plant-derived or fully synthetic materials. Correspondingly, it is or can be obtained in strictly vegan quality, respectively.
[0214] The vitamin D3-series is as known to the skilled person more metabolically active overall in terms of impacting PTH levels and possibly in terms of the number of genes impacted with regard to their expression by a given dose in vitro. One reason is that the structural difference in the sidechain impacts the activating 25- and the inactivating 24-hydroxylation. Furthermore, the DBP-complex is less stable in the D2-series, the induction of the 24-hydroxylating CYP24A1 is stronger in the D3-series and there is a statistically highly significant difference in timing as follows (cp. the already cited publication by Muhammad M. Hammami et al., BMC Endocr. Disord. 2017; 17: 12): Vitamin D2 results in a higher overall area under the curve (AUC) of 25(OH)D, if administered daily over many weeks, rather than 2- or 4-weekly as bolus, while the opposite holds for vitamin D3. This points to comparatively more accelerated deposition at elevated concentration in case of vitamin D2. It may in addition point to a less distinct feedback-suppression by elevated 25(OH)D blood levels of the release of adipocyte-bound vitamin D3 than vitamin D2.
[0215] Finally, it is reasonable to assume that there might be some differences of the two vitamins regarding their distribution in the organism. The combination of vitamin D2 and D3 shows less toxicity than straight additivity of the toxic effects of the two would predict. Dosing 25(OH)D plus the combined vitamins D2 and D3 to obese individuals will at comparatively low dose levels result in adequate supply of the required amounts of vitamin D to their different types of adipocytes and mitigate local overdosing. Dosing 25(OH)D plus vitamin D3 represents the supplementation approach of choice for overweight or obese individuals in environments of significant vitamin D2 fortification of food.
[0216] It is further noted that 25(OH)D3 and 25(OH)D2 plus vitamin D in combination may be more suitable than just one 25-hydroxylated metabolite plus vitamin D in view of the compromise to reach a reasonable vitamin D status and still enable some level of release of vitamin D from adipocytes.
[0217] The inventors compiled some essentially indirect evidence up to today for their in view of the state-of-the-art surprising conclusion that the relevant deposition of vitamin D in fatty tissues including lipid droplets is tissue-surface-based rather than tissue-mass-based. In addition, they pursue experiments targeting a direct proof of their conclusion, which may be compared with the above-mentioned observations concerning free cholesterol (already cited article by Susanne Prattes et al.). But they are not yet there, and the surface-based deposition is still to an extent a hypothesis. However, the inventors found that the experience that obese individuals need about 2.5 times the amount of vitamin D supplementation a normal individual needs to achieve a given level of 25(OH)D provides an independent basis to support their surprising supplementation- and dosage-related conclusions—and the dosage figures resulting are nicely comparable. Thus, it is proposed that the reasonable ratio of 25(OH)D to vitamin D to be preferentially supplemented for obese can be determined as follows. If one estimates that ⅔ of vitamin D administered to non-obese quickly finds its way from the lymph to the blood and that the rest ends up in adipose tissue (disregarding other compartments) and assuming that 100% of the administered vitamin D are actually absorbed (which is on the high side) and assuming that 600 I.U. per day is for sure a healthy supplementation, one can conclude that about 200 I.U. per day are going to the adipose tissue of non-obese. If one now supplements the 2.5-fold amount, viz. 1500 I.U. per day to an obese person, then 400 I.U. (the same amount as in normal subjects) will end up in the blood and will eventually be metabolized to 25(OH)D. But that means on the other hand that 1100 I.U. vitamin D per day is loaded into the adipose tissue of the obese person. In other words: about 66% of the administered vitamin D are eventually becoming 25(OH)D in the blood of non-obese, while only 26.66% of the administered vitamin D become 25(OH)D in the blood of obese. Therefore, based on the rule of thumb that obese persons need 2.5-times more vitamin D to get to the same adequate vitamin D-status (measured as 25(OH)D-level in blood) and assuming as above that 100% are absorbed from the gastrointestinal tract (GI-tract) then 5.5—times more vitamin D is ending up in the adipose tissue of an obese person compared to a non-obese person.
[0218] If finally assuming that zero vitamin D per day in the adipose tissue might be too little (in other words, that one should not exclusively supply 25(OH)D!), one might conclude that 200-400 I.U. vitamin D ending up per day in the adipose tissue of obese are fine or possibly even advantageous (200 I.U. were calculated above on the basis of a supplementation of 600 I.U. to a non-obese, and 400 I.U. might analogously still be fine in an obese who may, in comparison to the non-obese, have roughly the double amount of fatty tissue, and roughly the 1.5 times larger surface of fatty tissue). Thus, one might supplement obese by administering up to about 550 I.U. vitamin D per day (if 26.66% thereof are eventually becoming 25(OH)D, 73.33% are ending up in fatty tissue; and 73.33% of 550 I.U. are 400 I.U.—or precisely 403.15) and correct the resulting deficient blood level by dosing 25(OH)D in parallel, e.g. as well up to about 13.75 μg (viz. 1 μg vitamin D=40 I.U.) to make up for the fact that the absorption may not be complete. The administration of 550 I.U. of vitamin D results, based on the rule of thumb, in 26.66% in the blood of obese, corresponding to the formation of approx. 3.7 μg 25(OH)D; therefore, we lack approx. 6.3 μg 25(OH)D, which have to be supplemented as such. If we now supplement 13.75 μg 25(OH)D instead, we take into account that the enterohepatic up-take is probably lower than 100%, that approximately doubling that dose keeps us still very far away from a toxic dose, and that the obese might in addition be a bit heavier than the non-obese and accordingly have a statistically somewhat higher blood-volume. Overall, we stay on the careful side for the obese with regard to the case of vitamin D, where we do not want to overshoot and where we assume 100% up-take from the GI-tract, and we are somewhat more aggressive in the case of 25(OH)D, because we know that it has a nice therapeutic width and that it is not accumulating in fatty tissues.
[0219] Based on the above it is suggested that a combination of 25(OH)D2 and vitamin D3 or vitamin D2 or a combination of 25(OH)D3 and vitamin D3 or vitamin D2 is used for the treatment of and/or prophylaxis of vitamin D insufficiency or deficiency in obese persons, persons having the tendency to get obese or persons having a history of malabsorption of vitamin D. The ratio of the 25 hydroxy form of the vitamin D to vitamin D is in the range between 1 to 5 and 5 to 1, preferentially between 1 to 2 and 2 to 1, or in a ratio of 1 to 1, most preferably in a ratio selected from the group of 1 to 1, 1 to 1.5, 1 to 2, 1.5 to 1. Under certain circumstances (e.g. depending on the lifestyle—such as when a person has a high exposure of his skin to the sun) the supplementation of 25(OH)D2 and/or 25(OH)D3 may already be sufficient due to the endogeneous vitamin D3 production.
Example 1
[0220] The conclusions as presented herein are based on the following experiments: In a double-blinded cross-over study single high dosages (900 μg total in two soft gel capsules containing 450 μg) of either vitamin D3 or 25(OH)D3 were administered to vitamin D-deficient volunteers including healthy controls as well as subjects with a history of malabsorption. At the outset, the BMI was determined. Blood samples were then taken at baseline and at 2, 4, 6, 8, and 12 hours as well as 1, 2, 3, 7, and 14 days after administration (
[0221] The observed difference reflects the published (Hossein-nezhad A.; Mayo Clin. Proc. (July 2013); cited above) difference of the two substance types' main mechanisms of up-take from the gastro-intestinal tract: mainly lymphatic (in chylomicrons) in case of vitamin D and mainly enterohepatic (via portal vein) in case of 25(OH)D. But those different mechanisms of up-take do per se not explain the strong BMI-dependence of the appearance in blood of vitamin D and correspondingly its metabolite, 25(OH)D, after single doses of vitamin D as observed in our study: rapid and very distinct in case of BMI <20, less rapid and distinct in case of BMI greater than 20 up to a BMI about 30, and somewhat slower and strongly reduced in case of BMI higher than 30 (DiVasta A D, et al. J Clin Endocrinol Metab (August 2011); cited above).
[0222] There are several conceivable theoretical approaches to explaining this BMI-dependence. There are indications for a strongly uneven distribution to different fatty compartments of administered vitamin D and indications for a slower rate of release from these compartments into the bloodstream in obese as opposed to non-obese. Taken together, our observations and considerations lead to the following conclusions: [0223] a) It is too simplistic to just explain the reduced appearance of administered vitamin D in the blood of obese as compared to non-obese by referring to the obese subjects' comparatively higher amounts of total fatty tissue. Surface-dependent deposition, a certain feedback control by vitamin D metabolites of the release of vitamin D from adipocytes (possibly in part in metabolized form), and a role of the differences of the lymphatic systems of obese and non-obese persons are likely to contribute herein. [0224] b) It is very likely that significant accumulation and strongly elevated local concentrations of vitamin D in given populations of adipocytes or adipose tissues result, if administering to obese 2.5 to 3 or even more times the dose normally administered to non-obese. [0225] c) It is conceivable that this accumulation is in obese or potentially obese subjects (due to local metabolism) resulting in counterproductive or negative local effects, while there may still be absolutely no signs of systemic hypercalcemia because of the substances' very slow release from the respective sites (body fat pool).
[0226] As noted above vitamin D formulations for use in the treatment of persons with vitamin D deficiencies are commercially available for decades. Pharmaceutical compositions comprising 25(OH)D3 or 25(OH)D2 can be formulated by the skilled person in a similar way taking into account the information on the properties, specifications and characteristics of suitable excipients as described e.g. in standard texts such as Fiedler, H. P.; 1996; Lexikon der Hilfsstoffe for Pharmazie, Kosmetik und angrenzende Gebiete; Editio Cantor Verlag Aulendorf (Germany), and Kibbe, A. H.; 2000; Handbook of Pharmaceutical Excipients, a joint publication of Pharmaceutical Press, London (UK), and American Pharmaceutical Association, Washington (US) as well as manufacturers' brochures.
[0227] Immediate-release (IR) formulations of calcifediol (25(OH)D3) have been available for decades in the European Union (EU) for indications such as rickets, prevention of calcium disorders secondary to corticosteroid or anticonvulsant therapy and treatment of osteomalacia, renal osteodystrophy, hypoparathyroidism, familial hypo-phosphatemia and vitamin D malabsorption (see: Holick M F Binkley N C, Bischoff-Ferrari H A, Gordon C M, Hanley D A, Heaney R P, Murad M H and Weaver C M. “Evaluation, Treatment & Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline”; J Clin Endocrinol Metab. (July 2011) 96(7):1911-1930; Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2017; 7: 1-59).; Haddad J G, Jr. Rojanasathit S.; “Acute administration of 25-hydroxycholecalciferol in man” J. Clin Endocrinol Metabo (1976) 42:284-290; Bordier P J, Marie P J, Arnaud C D; “Evolution of renal osteodystrophy: correlation of bone histomorphometry and serum mineral and immune parathyroid hormone values before and after treatment with calcium carbonate or 25-hydroxycholecalciferol”; Kidney Int Suppl. (January 1975) 102-112).
[0228] In the US, IR calcifediol was marketed from 1980 to 2002 as Calderol™ for the treatment of metabolic bone disease in dialysis patients and was withdrawn from the market in 2002 for commercial reasons not associated with safety or efficacy. Calderol™ displayed pharmacokinetic (PK) characteristics consistent with an IR formulation, with the time (tmax) to reach maximum serum calcifediol concentrations (Cmax) occurring within 4 to 8 hours postdose (Haddad J G, Jr.; cited above). Published clinical studies have clearly shown that IR calcifediol increased serum 25(OH)D far more quickly and effectively than vitamin D supplements. Extended release calcifediol gradually releases calcifediol, increasing serum 25(OH)D at a slower rate than IR formulations (Sprague et al. 2017; cited above; Sprague et al. 2015; cited above).
[0229] Pharmaceutical compositions comprising a combination of 25(OH)D3 and 25(OH)D2; 25(OH)D3 and vitamin D3 or vitamin D2; or 25(OH)D2 and vitamin D3 or vitamin D2; or a combination of 25(OH)D3 or 25(OH)D2 and vitamin D3 and/or vitamin D2 can be prepared by the skilled person in similar way as described above.
[0230] The pharmaceutical compositions as described above may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Example 2
[0231] The pharmacokinetic parameters of orally administered 25(OH)D3 and vitamin D3 (both provided for formulation in form of visually identical soft-gel pills) were studied based on the corresponding serum concentration-time curves in healthy adults and adults with a history of intestinal malabsorption (see
[0232] Study outcomes measured are vitamin D and its major metabolite 25(OH)D, whereby the measurements were taken at various times over a 2-week period. Serum levels of calcium, phosphorus, albumin, creatinine and intact parathyroid hormone (iPTH) were determined at baseline and at the end of each 14-day pharmacokinetic study (see Table 4). The pharmacokinetic parameters have been determined by evaluating the serum concentration-time curves in patients with malabsorption syndrome and healthy controls (Tables 5 and 6).
[0233] The primary outcomes of the study are the serum pharmacokinetic parameters of 25(OH)D3 and vitamin D3 after a single oral administration of 900 μg of each in a double-blind randomized crossover study. The serum concentrations of vitamin D and 25(OH)D at various times were determined according to methods known in the art as the primary outcome measure.
[0234] The study (summarized in
[0235] Adult patients (18 years and older) with a history of intestinal malabsorption (n=10) and healthy adult volunteers (n=10); (of both sexes and all ethnicities) has been recruited in this randomized double-blinded crossover study. The BMI has been determined and recorded at baseline. All subjects have been prescreened for 25(OH)D levels to include subjects with 25(OH)D<30 ng/mL. The subjects have been randomized to receive two oral doses of 450 μg taken simultaneously (total 900 μg) of either vitamin D3 or 25(OH)D3. Blood samples were taken at baseline and at 2, 4, 6, 8, 12 hours and days 1, 2, 3, 7 and 14. There was a two weeks washout period before the subject received in a double blinded manner, two oral doses of 450 μg taken simultaneously (total 900 μg) of either 25(OH)D3 or vitamin D3 (depending on which one they took in the randomization) any time after the 2 week washout. Blood samples were taken at baseline and at 2, 4, 6, 8, 12 hours and days 1, 2, 3, 7 and 14 days. Serum levels of calcium, phosphorus, albumin, creatinine, and intact parathyroid hormone (iPTH) were obtained at baseline and at day 14 for each arm (or within a reasonable time if the study participant was unable to come on the exact day). Vitamin D and 25(OH)D were determined on all the blood samples collected at the various times.
[0236] The clinical study was performed taking into account the following potential risks and benefits. Pharmacokinetic studies have previously been performed with 25(OH)D3 given as a single 448 μg dose intravenously or as a single dose of 900 μg in a slow release formulation (Sprague et al. 2017; cited above). As can be seen in FIG. 3 of Sprague et al., the peak concentration of 25(OH)D increased by approximately 110 ng/mL and 10 ng/mL above the baseline after receiving the bolus intravenous dose of 448 μg or 900 μg of slow release 25(OH)D3, respectively. No toxicity was observed.
[0237] In the course of the present clinical study only those subjects were included who had a level of 25(OH)D<30 ng/mL. Therefore, it was concluded that an increase of as much as 110 ng/mL after a bolus intravenous dose which by 24 hours decreased to 40 ng/mL will not cause toxicity. Vitamin D intoxication is seen only when the 25(OH)D levels are sustained above 150 ng/mL for a prolonged period viz. usually several months. A single oral dose of 1250 μg of vitamin D once a week for 8 weeks or every 2 weeks for up to 6 years is not associated with toxicity (see: Holick M F et al.; J Clin Endocrinol Metab. (July 2011); cited above).
[0238] Safety issues are associated with the potential for vitamin D intoxication. Vitamin D intoxication is associated with hypercalcemia, hyperphosphatemia and suppressed PTH as noted by the Endocrine Society Practice Guidelines on Vitamin D (see: Holick M F et al.; J Clin Endocrinol Metab. (July 2011); cited above; and Kidney Disease Improving Global Outcomes (KDIGO) 2017 clinical practice guideline update for the diagnosis, evaluation, prevention and treatment of chronic kidney disease—mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017; 7: S1-S59). As all subjects involved in the study are vitamin D deficient or have insufficient levels of vitamin D (25(OH)D<30 ng/mL), it was presumed that they are not harmed by receiving single doses of both vitamin D3 and 25(OH)D3, because such treatment will rather help to improve their vitamin D status. Men and women who took 50,000 IU (1250 μg) vitamin D once a week for 8 weeks were able to maintain their serum 25(OH)D at >30 ng/mL without toxicity (Holick M F et al. (July 2011); cited above).
[0239] Study Subject Selection
[0240] Subject Inclusion Criteria [0241] 1. 18 years of age or older [0242] 2. Healthy male or female adults (for healthy control group) [0243] 3. Adult male or female patients with a history of intestinal malabsorption at the Boston University Medical Campus. [0244] 4. No medications or disorders that would affect vitamin D metabolism. [0245] 5. Taking vitamin D (ergocalciferol or cholecalciferol). Subjects taking vitamin D supplement of more than 2000 IUs (50 micrograms/day) that may interfere with study endpoints, must be willing and able to discontinue use of these supplements for the duration of the study and allow for at least a 14-day washout prior to enrollment. [0246] 6. Women must be on birth control and not pregnant based on a negative pregnancy test at baseline for each of the two pharmacokinetic studies. [0247] 7. Ability and willingness to give informed consent and comply with protocol requirements. [0248] 8. Serum total 25(OH)D<30 ng/mL.
[0249] Subject Exclusion Criteria [0250] 1. Use of supplemental dose of vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) daily equivalent (2,000 IU/50 μg) 1 week or less prior to randomization and during the study. [0251] 2. On medications that can affect vitamin D metabolism including steroids such as prednisone, anti-seizure medications and medications to treat HIV. [0252] 3. Tanning in a tanning bed at least one week before the study and throughout the duration of this study. [0253] 4. Anyone anticipating going on holiday (where exposure to sun is imminent) 1 week before or during the entire study. [0254] 5. Participation in the study or any reason which, in the opinion of the investigator, makes adherence to a treatment or follow-up schedule unlikely. [0255] 6. History of an elevated serum calcium. [0256] 7. Chronic hepatic or renal failure. [0257] 8. Subjects with a history of an adverse reaction to orally administered vitamin D. [0258] 9. Inability to give informed consent.
[0259] The subjects baseline characteristics are provided in the following Table 4.
TABLE-US-00004 TABLE 4 Baseline characteristics of healthy participants and patients with fat malabsorption Patients Healthy with fat participants malabsorption p- (N = 10) (N = 6) value Age 32.3 ± 2.7 46.5 ± 4.1 0.011* Number of female participants 8 (80%) 6 (100%) 0.500 Body mass index (kg/m.sup.2) 27.0 ± 2.1 32.7 ± 4.1 0.263 Ethnicity Caucasian 5 (50%) 4 (67%) Hispanic 0 (0%) 1 (17%) Asian 2 (20%) 0 (0%) Black 3 (30%) 1 (17%) Serum chemistry Vitamin D2 (ng/mL) 0.0 ± 0.0 0.0 ± 0.0 0.100 Vitamin D3 (ng/mL) 0.0 ± 0.0 1.6 ± 1.0 0.313 Total 25-hydroxyvitamin 17.1 ± 2.3 14.7 ± 3.4 0.958 D (ng/mL) 25-hydroxyvitamin D2 (ng/mL) 0.4 ± 0.4 4.2 ± 3.1 0.428 25-hydroxyvitamin D3 (ng/mL) 16.7 ± 2.1 10.5 ± 4.2 0.368 Intact PTH (pg/mL) 41.5 ± 5.4 74.0 ± 16.9 0.073 Total calcium (mg/dL) 9.4 ± 0.1 9.4 ± 0.1 0.875 Phosphate (mg/dL) 3.9 ± 0.3 4.0 ± 0.3 0.635 Creatinine (mg/dL) 0.8 ± 0.03 0.7 ± 0.04 0.147 eGFR (mL/min/1.73 m.sup.2) 106.8 ± 4.7 104.0 ± 6.7 0.792 Glucose (mg/dL) 83.1 ± 7.5 89.8 ± 8.8 0.263 Albumin (g/dL) 4.4 ± 0.08 4.1 ± 0.05 0.022* Total protein (g/dL) 6.9 ± 0.08 6.8 ± 0.2 0.635 Total bilirubin (mg/dL) 0.5 ± 0.09 0.5 ± 0.05 0.792 Alkaline phosphatase (U/L) 54.5 ± 4.8 88.5 ± 17.3 0.022* Aspartate 18.4 ± 1.6 18.7 ± 2.5 0.875 aminotransferase (U/L) Alanine aminotransferase (U/L) 15.6 ± 1.0 16.7 ± 4.1 0.958 Data are expressed as mean ± SEM or number of participants with %. *denotes statistically significant difference between groups (p < 0.05).
[0260] The individuals participating in the study had, after signing a consent form, been randomized by a computer randomization chart in a blinded manner to receive two oral doses of 450 μg taken simultaneously (total 900 μg) of either vitamin D3 or 25(OH)D3. Blood samples have been taken at baseline and at 2, 4, 6, 8, 12 hours and days 1, 2, 3, 7 and 14. After a washout period of at least 14 days (2 weeks) the subjects received in a double blinded manner two oral doses of 450 μg taken simultaneously (total 900 μg) of either 25(OH)D3 or vitamin D3 (depending on which one they took in the first randomization) any time after the washout. Blood samples were taken at baseline and at 2, 4, 6, 8, 12 hours and days 1, 2, 3, 7 and 14.
[0261] All subjects have been recruited either from the Boston University Medical Campus or from the Boston area using a flyer that was be posted for recruitment purposes. In collaboration with the Endocrine, Diabetes and Nutrition and Gastroenterology sections in the Department of Medicine and the Surgical Department of Boston University Medical Campus patients with a malabsorption syndrome were invited to participate in the study. All subjects have been prescreened for serum 25(OH)D levels and included if they were vitamin D deficient or insufficient viz. a 25(OH)D<30 ng/mL. (Holick et al JCEM 2011.; cited above).
[0262] Blinding of capsules was done by computer randomization and provided by the Investigational Pharmacy Service during the trial. All subjects and research staff involved in the clinical study were blinded during the clinical trial. The data were unblinded at the end of the data collection phase at the discretion of the Principal Investigator. There were no unforeseen medical circumstances which required the premature unblinding of participant data under any of the participant's health Assessment of Safety and Data Safety Monitoring Plan (DSMP). The major potential side effect is hypercalcemia, hyperphosphatemia and suppressed PTH level with a 25(OH)D>150 ng/mL. However, toxicity has never been reported after a single or multiple oral doses of 1250 μg vitamin D or after a dose of 900 μg 25(OH)D3.
[0263] For the pharmacokinetic evaluation the sample size for this pilot study was estimated to be 10 in each group (10 patients with malabsorption syndrome and 10 healthy control) based on Rochon's sample size computation method for repeated measurement experiments (for details see: Kloprogge F, Simpson J A, Day N P J, White N J, Tarning J. 1975; 102-112. “Statistical power calculations for mixed pharmacokinetic study designs using a population approach” AAPS J. (September 2014) 16(5):1110-1118. doi: 10.1208/s12248-014-9641-4. Epub 2014 Jul. 11.-14); Kang D, Schwartz J B, Verotta D. “Sample size computations for PK/PD population models” J Pharmacokinet Pharmacodyn. (December 2005) 32(5-6):685-701; Aarons L, Ogungbenro K. “Optimal design of pharmacokinetic studies” Basic Clin Pharmacol Toxicol. (March 2010); 106(3):250-255). Also considered were the data which were obtained from previous clinical trials for vitamin D3 and 25(OH)D3 (for details see: Lo C W et al.; cited above; Farraye F A, et al.; cited above; Sprague S M et al, 2017; cited above; Sprague S M, et al. 2015; cited above). This sample size of this study is expected to provide the power of >0.80.
[0264] Differences between treatment groups were analyzed by a one- or two-sided t-test, as appropriate, with statistical significance set at p<0.05. The pharmacokinetic (PK) parameters for baseline-corrected serum 25(OH)D and vitamin D will be derived using non-compartmental analysis. Area under the serum concentration-time curve (AUC) was estimated using the linear trapezoid rule. The t½ was calculated by determination of the elimination rate constant from concentration values in the follow-up period.
[0265] As expected, healthy adults were able to absorb both vitamin D3 and 25(OH)D3 as demonstrated by significant increases in the blood levels of vitamin D3 and 25(OH)D3 after receiving a single 900 μg oral dose of vitamin D3 and 25(OH)D3, respectively. (
[0266] More surprising was, finally, the finding illustrated by Table 6 and by
TABLE-US-00005 TABLE 5 Pharmacokinetic parameters of oral 900 μg vitamin D3 and oral 900 μg 25-hydroxyvitamin D3 in healthy participants and patients with fat malabsorption Patients Healthy with fat participants malabsorption p- (N = 10) (N = 6) value 900 μg vitamin D3 arm AUC (ng .Math. hr/mL) 3258 ± 496 1177 ± 425 0.022* C.sub.max (ng/mL) 53.5 ± 6.0 24.3 ± 8.4 0.016* T.sub.max (hr) 10.4 ± 0.7 11.3 ± 0.7 0.345 T.sub.1/2 (hr) 31.4 ± 3.3 28.7 ± 1.5 0.713 C.sub.trough (ng/mL) 0.3 ± 0.3 0.1 ± 0.1 0.220 900 μg 25-hydroxyvitamin D3 arm AUC (ng .Math. hr/mL) 3128 ± 545 2667 ± 735 0.562 C.sub.max (ng/mL) 23.1 ± 4.6 23.2 ± 6.8 1.000 T.sub.max (hr) 11.2 ± 4.1 5.3 ± 0.7 0.031* T.sub.1/2 (hr) 60.6 ± 7.9 65.7 ± 29.9 0.313 C.sub.trough (ng/mL) 6.1 ± 1.3 6.7 ± 1.5 0.875 Data are expressed as mean ± SEM. *denotes statistically significant difference between groups (p < 0.05). Abbreviations: AUC: area under the concentration-time curve; C.sub.max: maximal concentration; T.sub.max: time to maximal concentration; T.sub.1/2: elimination half-life; C.sub.trough: trough level at day 14
TABLE-US-00006 TABLE 6 Pharmacokinetic parameters of oral 900 μg vitamin D3 and oral 900 μg 25- hydroxyvitamin D3 in healthy participants with higher and lower body mass index Healthy Healthy participants participants with higher with lower BMI BMI p- (N = 5) (N = 5) value 900 μg vitamin D3 arm AUC (ng .Math. hr/mL) 2089 ± 547 4427 ± 350 0.016* C.sub.max (ng/mL) 44.4 ± 9.3 62.6 ± 5.7 0.310 T.sub.max (hr) 9.6 ± 1.0 11.2 ± 0.8 0.310 T.sub.1/2 (hr) 23.8 ± 3.1 39.0 ± 3.4 0.010* C.sub.trough (ng/mL) 0.0 ± 0.0 0.6 ± 0.6 0.690 900 μg 25-hydroxyvitamin D3 arm AUC (ng .Math. hr/mL) 2621 ± 855 3633 ± 690 0.421 C.sub.max (ng/mL) 21.4 ± 8.0 24.8 ± 5.5 0.548 T.sub.max (hr) 15.2 ± 8.2 7.2 ± 0.5 0.841 T.sub.1/2 (hr) 55.0 ± 10.7 66.2 ± 12.3 1.000 C.sub.trough (ng/mL) 4.6 ± 1.4 7.6 ± 2.1 0.421 Data were expressed as mean ± SEM. *denotes statistically significant difference between groups (p < 0.05). Abbreviations: AUC: area under the concentration-time curve; C.sub.max: maximal concentration; T.sub.max: time to maximal concentration; T.sub.1/2: elimination half-life; C.sub.trough: trough level at day 14; BMI: body mass index
[0267] The study has been conducted according to applicable US federal regulations and institutional policies (which are based in federal regulations, guidance, and ICH Good Clinical Practice guidelines) after approval of the protocol and any amendments by the Boston Medical Center and Boston University Medical Campus IRB. If in the course of the study unanticipated problems, safety monitor's reports and adverse events occurred they were reported in line with the internal regulations at BMC/BU Medical Center IRB in line with the general IRB policies applicable for such studies. Where necessary appropriate steps were taken to ensure the well-being, safety and integrity of the participating subjects. Data handling and record keeping was made in line internal regulations at BMC/BU Medical Center taking into account the corresponding government regulations.
[0268] Based on the above clinical study the inventors come to the following conclusions and recommendations in connection with the treatment of vitamin D deficiencies: [0269] Obese (or overweight) persons or persons with a respective genetic disposition to get obese need more vitamin D than “normal ones”. [0270] It is known that when the high amounts of vitamin D they need to get a reasonable blood level of 25(OH)D are administered to such persons most of the vitamin D ends up in their fatty tissues. While such heavy load does not manifest itself in clearly observable systemic toxic effects, it cannot be excluded that some negative or counterproductive effects may occur locally (e.g. in the fatty tissue). [0271] In addition, the uptake of vitamin D from lymph to blood is probably reduced in obese persons, persons having the tendency to get obese and in persons having a history of malabsorption of vitamin D or persons with a genetic disposition to develop obesity. [0272] Based on the above it would seem logic to just supplement 25(OH)D to such persons. Quite clear by now is that an approximate blood level of 25(OH)D>30 ng/mL should be targeted. However, there is an aspect which is a priori unrelated to the above, namely that there is increasing evidence that vitamin D per se may have additional favourable biological activities (e.g. in stabilizing cell membranes) besides the fact that in general it is metabolized in the liver to 25(OH)D and then to the vital 1,25(OH)2D in the kidney. The latter metabolite is known to regulate more than 700 genomically controlled processes. [0273] This growing evidence of favourable effects of vitamin D3 and D2 per se puts a question mark behind supplementing just 25(OH)D to obese who are in the average anyway having less vitamin D3 and D2 per se in their blood than people with lower BMI. [0274] Therefore, if just this aspect is considered, it would appear to be logical to supplement even more vitamin D to obese than to non-obese. [0275] The two above groups of arguments seem to be directed to contradictory solutions of the problem to treat vitamin D deficiencies, particularly in obese persons, overweight persons having the tendency to get obese or persons having a history of malabsorption of vitamin D or persons with a genetic disposition to develop obesity. One solution points to administering as little vitamin D3 and D2 per se as possible. The other solution points to administering by all means not too little vitamin D3 and D2 per se. [0276] In contrast to the case of 25(OH)D the ideal “blood level” of vitamin D3 and/or D2 per se, is in essence still unknown. The reason is, e.g., that there is much less of a constant “level” of vitamin D3 and D2 per se in comparison to 25(OH)D, because the former has a much shorter T.sub.1/2 than the latter and in addition less affinity to the binding protein (DBP) in the blood and a higher tendency to disappear in the fat—besides the fact that its concentration is in addition lower in the average. Accordingly, one consideration is that periodic peaks of vitamin D3 and D2 per se are what the organism needs. The other consideration is that one has to take into account that the skin, where vitamin D3 is naturally formed, can actually be regarded like a slow release compartment. [0277] Finally, a point regarding analytics: One is routinely analysing 25(OH)D in blood, because it is less “jumpy” than vitamin D3 and D2 per se, the average concentration is higher, and the assay is well established. Nevertheless, it is also possible to measure vitamin D3 and D2 per se in serum as it is described above. [0278] The above conclusions point towards the solution that vitamin D insufficiencies or deficiencies, particularly in obese persons, overweight persons having the tendency to get obese or persons having a history of malabsorption of vitamin D or persons with a genetic disposition to develop obesity should be treated with (i) a combination of 25(OH)D3 and/or 25(OH)D2 and vitamin D2; or (ii) a combination of 25(OH)D3 and/or 25(OH)D2 and vitamin D3; or (iii) a combination of 25(OH)D3 and/or 25(OH)D2 and a combination of vitamin D2 and vitamin D3 in a BMI-dependent way, whereby also lifestyle factors and/or diet factors are to be considered. Some people may not need the added vitamin D3 and D2 per se, because of their lifestyle provides them with sufficient vitamin D production in the skin and/or their dietary uptake of vitamin D provides them a sufficient level of vitamin D. Another point to take into account is that some obese persons may a priori have a comparatively high blood level of 25(OH)D and correspondingly do need less or no supplementation of 25(OH)D: Other obese persons who are low on 25(OH)D need a corresponding amount of 25(OH)D being supplemented. In cases where an obese person is just slightly low in 25(OH)D supplementing 25(OH)D alone might do, because this “comparatively high level” of 25(OH)D is indicating that vitamin D3 and D2 per se won't be very low either. In rare cases the 25(OH)D level is in the ideal range and thus no 25(OH)D must be supplemented.