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.

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.

Effect of 1-year oral cholecalciferol on a metabolic profile and blood pressure in poor-controlled type 2 diabetes mellitus: an open-label randomized controlled pilot study.

PURPOSE: Hypovitaminosis D has been associated with many cardio-metabolic disorders, although their pathogenetic link still remains unclear. Our aim was to evaluate whether 1-year vitamin D (D) supplementation could improve glycemic control, lipid profile, systolic (SBP) and diastolic (DBP) blood pressure levels and body composition. METHODS: In an open-label randomized-controlled pilot study, thirty poor-controlled (HbA1c > 59 mmol/mol) type 2 diabetic patients (age 71.5 ± 3.2 years, M/F 21/9, BMI 29.8 ± 3.6 kg/m2) with hypovitaminosis D (25OHD 22.0 ± 11.3 nmol/l) were randomized to cholecalciferol supplementation (500 UI/kg p.o. weekly, + D) or observation (- D) for one year. Changes in parameters of glucose, lipid and blood pressure control at 3, 6, 9 and 12 months vs. baseline were assessed. RESULTS: One-year D supplementation restored D status and had a beneficial effect on fasting glucose (FG, mean percentage changes ± SD, - 1.8% ± 23.1 vs. + 18.8% ± 30.0), glycosylated haemoglobin (HbA1c, - 13.7% ± 14.5 vs. - 4.2% ± 14.1), SBP (- 13.4% ± 8.5 vs. - 2.4% ± 12.6) and HDL-cholesterol levels (- 2.1% ± 14.0 vs. - 10.9% ± 12.9; p < 0.05 for all comparisons) in + D vs. - D patients, respectively. In the former, a reduction in HBA1c, SBP and DBP levels, BMI, fat mass index (FMI) and ratio (FMR) was observed after 1 year (p < 0.05 for all comparisons vs. baseline). We noticed a relationship between 1-year mean percentage changes of serum 25OHD and SBP levels (R = - 0.36, p < 0.05). CONCLUSION: One-year cholecalciferol supplementation, able to restore D status, significantly improves FG, HbA1c, SBP and HDL-cholesterol levels in patients with poor-controlled type 2 diabetes mellitus and D deficiency.

Flash Fabrication of Orally Targeted Nanocomplexes for Improved Transport of Salmon Calcitonin across the Intestine.

Salmon calcitonin (sCT) is a potent calcium-regulating peptide hormone and widely applied for the treatment of some bone diseases clinically. However, the therapeutic usefulness of sCT is hindered by the frequent injection required, owing to its short plasma half-life and therapeutic need for a high dose. Oral delivery is a popular modality of administration for patients because of its convenience to self-administration and high patient compliance, while orally administered sCT remains a great challenge currently due to the existence of multiple barriers in the gastrointestinal (GI) tract. Here, we introduced an orally targeted delivery system to increase the transport of sCT across the intestine through both the paracellular permeation route and the bile acid pathway. In this system, sCT-based glycol chitosan-taurocholic acid conjugate (GC-T)/dextran sulfate (DS) ternary nanocomplexes (NC-T) were produced by a flash nanocomplexation (FNC) process in a kinetically controlled mode. The optimized NC-T exhibited well-controlled properties with a uniform and sub-60 nm hydrodynamic diameter, high batch-to-batch reproducibility, good physical or chemical stability, as well as sustained drug release behaviors. The studies revealed that NC-T could effectively improve the intestinal uptake and permeability, owing to its surface functionalization with the taurocholic acid ligand. In the rat model, orally administered NC-T showed an obvious hypocalcemia effect and a relative oral bioavailability of 10.9%. An in vivo assay also demonstrated that NC-T induced no observable side effect after long-term oral administration. As a result, the orally targeted nanocomplex might be a promising candidate for improving the oral transport of therapeutic peptides.

Pharmacokinetics of a New Pharmaceutical Form of Vitamin D3 100,000 IU in Soft Capsule.

Vitamin D deficiency is frequent in the general population and both subjects and health professionals could benefit from a broader range of vitamin D3 formulations. We conducted a single-dose, open-label, parallel-group, randomized bioequivalence study to compare a single dose of a newly developed vitamin D3 100,000 IU in a soft capsule (Group 1) with the reference drug vitamin D3 100,000 IU oral solution in ampoule (Group 2) in healthy volunteers over a four-month period. The primary endpoint was the area under the curve (AUC) of serum 25-hydroxyvitamin-D (25(OH)D) concentrations on Day 112. This study was conducted in France from February to June 2014 in 53 young adults with a mean age of 26.9 years. At baseline, low mean serum 25(OH)D levels were observed in both groups (10.6 ng/mL in Group 1 and 9.0 ng/mL in Group 2). On Day 112, the AUC of serum 25(OH)D concentration was 2499.4 ± 463.8 nmol/mL (7.8 ± 0.2 for LogAUC) for Group 1 and 2152.3 ± 479.8 nmol/mL (7.6 ± 0.2 for LogAUC) for Group 2. Bioequivalence of the two treatments was not demonstrated. Superiority of vitamin D3 100,000 IU soft capsule was observed with p = 0.029 for AUC and p = 0.03 for LogAUC using a non-parametric Wilcoxon test. The profile of the serum 25(OH)D concentration showed a significant difference in favor of Group 1 on Days 1, 3, 7, 14 and 90. Mean serum 25(OH)D concentrations in Group 1 were between 20 and 30 ng/mL during the four-month period and under 20 ng/mL throughout the study in Group 2, except on Day 112. Mean Cmax for Group 1 was significantly higher (p = 0.002). Fourteen days were needed to reach Tmax by more than half the subjects in Group 1 compared to 45 days in Group 2. Both treatments were well tolerated, with no severe or related adverse events reported. In conclusion, the pharmacokinetic profile of the new formulation of vitamin D3 100,000 IU soft capsule is superior to that of the oral solution in ampoule. The new formulation increased serum 25(OH)D levels to above 20 ng/mL and maintained levels from 20 ng/mL to 30 ng/mL for four months in late winter and spring.