Personalise vitamin D3 using physiologically based pharmacokinetic modelling.

Plasma concentration of vitamin D3 metabolite 25-hydroxyvitamin D3 (25(OH)D3 ) is variable among individuals. The objective of this study is to establish an accurate model for 25(OH)D3 pharmacokinetics (PKs) to support selection of a suitable dose regimen for an individual. We collated vitamin D3 and 25(OH)D3 plasma PK data from reported clinical trials and developed a physiologically-based pharmacokinetic (PBPK) model to appropriately recapitulate training data. Model predictions were then qualified with 25(OH)D3 plasma PKs under vitamin D3 and 25(OH)D3 dose regimens distinct from training data. From data exploration, we observed the increase in plasma 25(OH)D3 after repeated dosing was negatively correlated with 25(OH)D3 baseline levels. Our final model included a first-order vitamin D3 absorption, a first-order vitamin D3 metabolism, and a nonlinear 25(OH)D3 elimination function. This structure explained the apparent paradox. Remarkably, the model accurately predicted plasma 25(OH)D3 following repeated dosing up to 1250 µg/d in the test set. It also made sensible predictions for large single vitamin D3 doses up to 50,000 µg in the test set. Model predicts 10 µg/d regimen may be ineffective for achieving sufficiency (plasma 25(OH)D3 ≥ 75 nmol/L) for a severely deficient individual (baseline 25(OH)D3 = 10 nmol/L), and it might take the same person over 200 days to reach sufficiency at 20 µg/d dose. We propose to personalize vitamin D3 supplementation protocol with this PBPK model. It would require measuring 25(OH)D3 baseline levels, which is not routinely performed under the current UK public health advice. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin D PK exhibits substantial inter-individual variability. Different officially recommended daily doses are confusing. ​ WHAT QUESTION DID THIS STUDY ADDRESS? Is the UK's recommended 10 µg daily dose sufficient? Should everyone be given same dose? ​ WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our model accurately predicts plasma 25(OH)D under daily oral administration of vitamin D3 . The 10 µg daily vitamin D3 dose is insufficient for prophylaxis (plasma 25(OH)D at 75 nmol/L). ​ HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? Combining blood test to measure 25(OH)D baseline with this PBPK model will help inform dosage selection and select follow-up date to improve effectiveness of Hypovitaminosis D treatment.

Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.

PURPOSE: To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population. METHODS: All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression. RESULTS: Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [CI 95% 0.91-0.98], p = 0.004). Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients (56/9474 [0.6%] vs 96/7616 [1.3%]; HR 0.66 [CI 95% 0.46-0.93], p = 0.018). Calcifediol use (n = 134,703) was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements (88/16276 [0.5%] vs 96/7616 [1.3%]; HR 0.56 [CI 95% 0.42-0.76], p < 0.001). CONCLUSIONS: In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.