Pharmacokinetics Modelling Reveals Inconsistency Between the US and European Vitamin D Safety Guidelines.

Background: For vitamin D, the US National Academies of Sciences, Engineering, and Medicine (NASEM) suggest serum 25-hydroxyvitamin D (25(OH)D) >125 nmol/L is linked to potential toxicity. The European Food Safety Authority (EFSA) recommends that daily doses up to 2000 IU (50 µg) are safe for children aged 1-10 years, and 4000 IU (100 µg) for those aged 11 years and over. We evaluated the consistency between these two guidelines. Methods: We compiled accessible under 18's clinical trial data for external validation. We tested published physiologically based pharmacokinetic (PBPK) models. We used simulations to explore the serum 25(OH)D pharmacokinetic profiles in children (6-10) and adolescents (11-17). We fitted a new model to the external validation data. Results: Our PBPK model, previously developed for healthy adults, made good predictions for the mean of the validation data. Model simulations suggested the mean should attain serum 25(OH)D > 115 nmol/L among 6-year-old children who take 2000 IU daily, and >125 nmol/L for 11- to 12-year-olds who take 4000 IU daily. We also presented clinical data to demonstrate that 4000 IU daily dosing increased serum 25(OH)D >125 nmol/L in a large proportion of healthy adults. Model parameters for the Cape Town children and the US and European children are different. Conclusions: This analysis highlights the inconsistency between the NASEM and EFSA guidelines and warrants the need for further pharmacokinetic modelling work to support the development of vitamin D safety parameters and guidelines. Our modelling suggests that the currently adopted 125 nmol/L threshold may warrant re-evaluation, as the supporting evidence appears heterogeneous and limited.