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

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. Simulations were performed to test the model on 463 other participants in the same trial, and in a cohort of 1871 Mongolian schoolchildren aged 6-14 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 same Cape Town trial (mean 25.8 nmol/L, 95% CI: [8.3-47.2] nmol/L), the 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. Despite a higher weekly dose (14,000 IU), the Mongolian children demonstrated a smaller average increase in serum 25(OH)D3 (23.3 [-24.5, 83.1] nmol/L), and 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 increases than Mongolian children.