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Personalise vitamin D₃ using physiologically based pharmacokinetic modelling.

ABSTRACT: 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.

SUBMITTER: Huang Z

PROVIDER: S-EPMC8302240 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

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Personalise vitamin D₃ using physiologically based pharmacokinetic modelling.

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