A pilot-randomized, double-blind crossover trial to evaluate the pharmacokinetics of orally administered 25-hydroxyvitamin D3 and vitamin D3 in healthy adults with differing BMI and in adults with intestinal malabsorption

Abstract

Background: Obese and malabsorptive patients have difficulty increasing serum 25-hydroxyvitamin D [25(OH)D] after taking vitamin D supplementation. Since 25(OH)D is more hydrophilic than vitamin D, we hypothesized that oral 25(OH)D supplementation is more effective in increasing serum 25(OH)D concentrations in these patients.

Objectives: We aimed to investigate the pharmacokinetics of oral 25-hydroxyvitamin D3 [25(OH)D3] and oral vitamin D3 in healthy participants with differing BMI and malabsorptive patients.

Methods: A randomized, double-blind crossover trial was performed in 6 malabsorptive patients and 10 healthy participants who were given 900 µg of either vitamin D3 or 25(OH)D3 orally followed by a pharmacokinetic study (PKS). After ≥28 d from the first dosing, each participant returned to receive the other form of vitamin D and undergo another PKS. For each PKS, serum vitamin D3 and 25(OH)D3 were measured at baseline and at 2, 4, 6, 8, and 12 h and days 1, 2, 3, 7, and 14. Pharmacokinetic parameters were calculated.

Results: Data were expressed as means ± SEMs. The PKS of 900 µg vitamin D3 revealed that malabsorptive patients had 64% lower AUC than healthy participants (1177 ± 425 vs. 3258 ± 496 ng · h/mL; P < 0.05). AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.540). The 10 healthy participants were ranked by BMI and categorized into higher/lower BMI groups (5/group). The PKS of 900 µg vitamin D3 showed that the higher BMI group had 53% lower AUC than the lower BMI group (2089 ± 490 vs. 4427 ± 313 ng · h/mL; P < 0.05), whereas AUCs of 900 µg 25(OH)D3 were not significantly different between the 2 groups (P = 0.500).

Conclusions: Oral 25(OH)D3 may be a good choice for managing vitamin D deficiency in malabsorption and obesity. This trial was registered at clinicaltrials.gov as (NCT03401541.

Keywords: 25-hydroxyvitamin D; bioavailability; clinical trial; intestinal malabsorption; obesity; vitamin D.

© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1

Schematic representation of the study showing the number of healthy participants and patients with intestinal malabsorption of vitamin D screened and randomly assigned in the 2 arms of the study. 25(OH)D, 25-hydroxyvitamin D; 25(OH)D3, 25-hydroxyvitamin D3.

FIGURE 2

(A) Mean ± SEM change in serum vitamin D3 concentration versus time curve after a single dose of oral 900 µg vitamin D3 in healthy participants (n = 10) and patients with intestinal malabsorption of vitamin D (n = 6). Using the Mann-Whitney U test, healthy participants had a statistically significantly higher AUC of serum vitamin D3 after ingesting 900 µg vitamin D3 compared with malabsorptive patients (mean ± SEM AUC: 3258 ± 496 vs. 1177 ± 425 ng · h/mL; P = 0.022). The difference remained significant in the ANCOVA model after adjustment for potential confounders, including age, BMI, and baseline serum total 25-hydroxyvitamin D, albumin, alkaline phosphatase, and intact parathyroid hormone concentrations (P = 0.029). (B) Mean ± SEM change in serum 25-hydroxyvitamin D3 concentration versus time curve after a single dose of oral 900 µg 25-hydroxyvitamin D3 in healthy participants (n = 10) and patients with intestinal malabsorption of vitamin D (n = 6). Using the Mann-Whitney U test, there was no statistically significant difference in AUC of serum 25-hydroxyvitamin D3 after ingesting 900 µg vitamin D3 between healthy participants and malabsorptive patients (mean ± SEM AUC: 3128 ± 545 vs. 2667 ± 735 ng · h/mL; P = 0.562). The difference remained nonsignificant in the ANCOVA model after adjustment for potential confounders, including age, BMI, and baseline serum total 25-hydroxyvitamin D, albumin, alkaline phosphatase, and intact parathyroid hormone concentrations (P  = 0.540). Reproduced with permission; copyright Holick, 2021.

FIGURE 3

(A) Mean ± SEM change in serum vitamin D3 concentration versus time curve after a single dose of oral 900 µg vitamin D3 in healthy participants with higher BMI (n = 5) and lower BMI (n = 5). Using the Mann-Whitney U test, healthy participants with a higher BMI [mean ± SEM (kg/m2): 31.4 ± 2.6] had a statistically significantly lower AUC of serum vitamin D3 after ingesting 900 µg vitamin D3 compared with those with a lower BMI (mean ± SEM: 22.6 ± 1.7; mean ± SEM AUC: 2089 ± 490 vs. 4427 ± 313 ng · h/mL; P = 0.016). However, there was no significant difference between the 2 groups in the ANCOVA model after adjustment for potential confounders, including age, BMI, and baseline serum total 25-hydroxyvitamin D, albumin, alkaline phosphatase, and intact parathyroid hormone concentrations (P = 0.244). (B) Mean ± SEM change in serum 25-hydroxyvitamin D3 concentration versus time curve after a single dose of oral 900 µg 25-hydroxyvitamin D3 in healthy participants with a higher BMI (n = 5) and lower BMI (n = 5). Using the Mann-Whitney U test, there was no significant difference in AUC of serum 25-hydroxyvitamin D3 after ingesting 900 µg vitamin D3 between healthy participants with a lower BMI (mean ± SEM: 22.6 ± 1.7) and those with a higher BMI (mean ± SEM: 31.4 ± 2.6; mean ± SEM AUC: 2621 ± 765 vs. 3633 ± 616 ng · h/mL; P = 0.421). The difference remained nonsignificant in the ANCOVA model after adjustment for potential confounders, including age, BMI, and baseline serum total 25-hydroxyvitamin D, albumin, alkaline phosphatase, and intact parathyroid hormone concentrations (P  = 0.500). Reproduced with permission; copyright Holick, 2021.

FIGURE 4

Mean ± SEM serum 25-hydroxyvitamin D3 concentration versus time curve after a single dose of oral 900 µg vitamin D3 or 25-hydroxyvitamin D3 in healthy participants (n = 10) and patients with intestinal malabsorption of vitamin D (n = 6). Using the Wilcoxon signed-rank test, the AUC of 25(OH)D3 for the 25(OH)D3 arm was statistically significantly higher than the AUC of 25(OH)D3 for the vitamin D3 arm in both healthy participants (mean ± SEM: 3128 ± 545 vs. 1463 ± 331 ng · h/mL; P < 0.001) and malabsorptive patients (mean ± SEM: 2667 ± 735 vs. 1491 ± 473 ng · h/mL; P < 0.001). 25(OH)D3, 25-hydroxyvitamin D3. Reproduced with permission; copyright Holick, 2021.

FIGURE 5

Mean ± SEM serum concentrations of 25(OH)D3 and vitamin D3 in all participants (n = 16) after oral administration of 900 µg 25-hydroxyvitamin D3 and 900 µg vitamin D3. The mean serum 25(OH)D3 concentration reached its maximal level at ∼8 h, which was 4 h earlier than the mean serum vitamin D3 concentrations after the oral administration of 900 µg 25(OH)D3 and 900 µg vitamin D3, respectively. Using the Wilcoxon signed-rank test, there was a significant difference in Tmax of vitamin D3 compared with Tmax of 25(OH)D3 for all participants (9.0 ± 2.6 vs. 10.8 ± 4.5 h; P = 0.015). Tmax, time to maximal concentration; 25(OH)D3, 25-hydroxyvitamin D3. Reproduced with permission; copyright Holick, 2021.