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Background and Aim: Vitamin D3 (i.e. cholecalciferol) produces an active metabolite 25-hydroxyvitamin D3 (i.e. 25(OH)D3) to promote intestinal calcium absorption. Given high population heterogeneity in 25(OH)D3 plasma concentration profiles, vitamin D3 dose regimen needs to be personalised. The objective of this study is to establish a model that accurately predicts 25(OH)D3 pharmacokinetics (PK) on an individual level to enable selection of an appropriate dose regimen for anyone. Methods: Plasma or serum concentrations of Vitamin D3 and 25(OH)D3 from different trials were compiled together. We then developed a series of Physiologically-Based Pharmacokinetic (PBPK) models for vitamin D3 and 25(OH)D3 in a stepwise manner to select the best model to optimally recapitulate the 10g and 100g daily dose data. Each arm of the clinical trials was simulated individually. Model predictions were qualified with PK data at other doses. Results: From data exploration, we observed an interesting phenomenon: the increase in plasma 25(OH)D3 after repeat dosing was negatively correlated with 25(OH)D3 baseline levels. Our final model assumes a first-order vitamin D3 absorption, linear vitamin D3 elimination and a non-linear 25(OH)D3 elimination which is described with an Emax function. This model offers a simple explanation to the apparent paradox: the negative correlation might arise from the non-linear 25(OH)D3 elimination process. The model was also able to accurately predict plasma 25(OH)D3 after repeat dosing at daily doses other than 10g and 100g, which was reassuring. Conclusions: We developed a PBPK model to recapitulate PK of plasma vitamin D3 and 25(OH)D3. A personalised vitamin D3 supplementation protocol requires measurement of 25(OH)D3 baseline levels. This should be tested in the clinics for each individual.
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?:doi
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10.1101/2020.12.06.20244897
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document_parses/pdf_json/f523ae96c82e5bce3b4d36d03f7f491a4a52fa35.json
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Personalise Dose Regimen of Vitamin D3 Using Physiologically-Based Pharmacokinetic Modelling
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