
Personalise Vitamin D.
DOSE REGIMEN DESIGN BY PBPK MODELLING
Accepted Article
Huang ZH and You T. (2021) Personalise Vitamin D3 Using Physiologically-Based Pharmacokinetic Modelling. CPT: Pharmacometrics & Systems Pharmacology. PDF
Download model in R, training data and test data in the zip archive in Supporting Information
App: https://beyond.shinyapps.io/vitamind3/
Why Vitamin D ?
Vitamin D is important
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Vitamin D is essential for intestinal calcium absorption and bone health.
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Vitamin D may play potential roles in the prevention of osteoporosis, cancer, diabetics, autoimmune disease and COVID-19 (Benskin, 2020)
Vitamin D deficiency is common all around the world
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Target: serum 25(OH)D level ≥75 nmol/L (25(OH)D is an active metabolite of vitamin D)
Severely deficient: < 30 nmol/L (FNB & IOM, 1997)
Deficient: 30 – 49 nmol/L (IOM, 2011)
Insufficient: 50 – 74 nmol/L (Holick, 2007)
Target for prevention: ≥ 75 nmol/L (Holick, 2007)
Danger of toxicity: > 250 nmol/L
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In North America, the prevalence of severe vitamin D deficiency increased to 10% in 2001-2006: the elderly, pregnant women, the black community and obese population accounted for a large proportion (Ganji et al, 2012)
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In Europe, vitamin D deficiency in most countries were over 20%, except some Nordic countries: traditional diet of cod and cod liver in Nordic regions is speculated to explain such difference (Feldman et al, 2018)
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In the UK, National Dietary and Nutrition Survey shows higher prevalence of hypovitaminosis D (marked by serum 25(OH)D < 40nmol/L) in the north of UK than the south, and the prevalence of hypovitaminosis D in most regions are higher than 30% in spring (Hyppönen et al, 2007)
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Serum 25(OH)D was poor in the elderly
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Low serum 25(OH)D has also been observed in UK adolescents
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What are the main challenges?
Guidelines for daily vitamin D intake issued by different countries are different
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US: Recommended Dietary Allowance (RDA) proposed by Institute of Medicine (IOM) (Ross et al, 2011)
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Target levels: 25(OH)D ≥ 50 nmol/L
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600 IU/d for 1 to 70 years old
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800 IU/d for 71 years old and over
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UK: Reference Nutrient Intake (RNI) proposed by Scientific Advisory Committee on Nutrition (SACN, 2016)
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Target levels: 25(OH)D ≥ 25 nmol/L
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400 IU per day all year round for the general UK population, including pregnant and lactating women and people at increased risk of vitamin D deficiency
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No model is accurate enough to help one effectively achieve sufficiency with the right dose and schedule
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Many clinical trials have been performed all over the world, yet data not readily available
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No model can accurately predict vitamin D pharmacokinetics in a person
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Some models are poorly calibrated and unreliable: overfitted with many implicit assumptions not supported by evidence (Sawyer et al, 2015)
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A nonlinear mixed effects model could only recapitulate limited doses and could not generate reliable prediction for an individual: the modelling attributes differences among individuals to random errors and do not attempt to understand the differences to make accurate predictions
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What have we done?
We made high quality data readily available
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We found over 100 trials from peer-reviewed publications as credible sources of information: the majority was randomised control trials to guarantee quality
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We put in huge efforts to digitise the graphs to tabulate the values for modelling
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We filled in the missing metadata in line with with the best practice to curate the most comprehensive, up-to-date and high quality dataset that characterise vitamin D pharmacokinetics (PK)
We built a novel physiologically-based pharmacokinetics (PBPK) model that is truly predictive
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Our data exploration highlighted baseline 25(OH)D serum levels were connected with PK
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We only used a subset of data to identify the right structure and right parameters of a model
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Our PBPK model most economically represented a simple hypothesis for this observation
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This model accurately predicted 25(OH)D PK at doses far higher than the training set (i.e. >2500 µg)
Our work will help millions achieve vitamin D sufficiency
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Our modelling made it possible to predict unique PK in an individual for the first time
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A serological test in conjunction with our modelling may enable personalise vitamin D
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Assess suitability of any dose regimen for helping an individual achieve optimal vitamin D
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Estimate the time it takes to reach target 25(OH)D level in order to schedule follow up blood test
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Predict 25(OH)D levels in real world situations that involve missing doses and drug holidays to ensure compliance
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Want to access our data?
Data set we compiled are available for academic and commercial purposes.
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If your email meets all requirements, we will schedule an online meeting to discuss the way forward.