Physiologically Based Pharmacokinetic Modelling of Serum 25-Hydroxyvitamin D Concentrations in Schoolchildren Receiving Weekly Oral Vitamin D3 Supplementation

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Abstract
Background: Following vitamin D3 oral administration, attained serum concentrations of its metabolite 25-hydroxyvitamin D3 (25(OH)D3) are variable among children. Methods: We developed physiologically based pharmacokinetic (PBPK) modelling using annually measured serum 25(OH)D3 concentrations in 77 Cape Town schoolchildren aged 6–11 years who received weekly oral doses of 10,000 IU vitamin D3 for 3 years during a clinical trial (Δ25(OH)D = 32.2 nmol/L, 95% CI: [−3.2, 65.8] nmol/L). Simulations were performed to test the model on 463 other participants in the same trial, and in a cohort of 1756 Mongolian schoolchildren aged 6–11 years who received weekly oral doses of 14,000 IU vitamin D3 for 3 years in another trial. Results: The best model attributed most of the variability in post-supplementation 25(OH)D3 concentrations to hepatic clearance and covariates including weight (ΔAIC = −21) and ZBMI (body mass index Z-score, ΔAIC = −34). For 463 other children from the Cape Town trial (Δ25(OH)D = 25.8 nmol/L, 95% CI: [8.3, 47.2] nmol/L), mean estimation error was 5.3 nmol/L, and 76.7% of observations were within the 95% prediction intervals. Our simulation supported the previous proposal that serum 25(OH)D3 should exceed 50 nmol/L among 97.5% of European children at 24.4 μg/day vitamin D3 dosing. At a higher weekly dose (14,000 IU), the Mongolian children demonstrated a higher average increase in serum 25(OH)D3 (40.6 [−2.9, 88.9] nmol/L) but were overestimated by the model. Conclusion: We developed the first PBPK model to successfully predict the long-term serum 25(OH)D3 increases in healthy schoolchildren in Cape Town who received orally administered vitamin D3 and exhibited higher relative increases than Mongolian children.
Funding Information
  • the Royal Golden Jubilee Ph.D. Programme in Thailand (PHD/0095/2561)
  • Medical Research Council (MR/R023050/1)
  • Medical Research Council (MR/M026639/1)
  • United States National Institutes of Health (1R01HL122624-01)

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