A physiologically based pharmacokinetic model of vitamin D

Abstract

Despite the plethora of studies discussing the benefits of vitamin D on physiological functioning, few mathematical models of vitamin D predict the response of the body on low-concentration supplementation of vitamin D under sunlight-restricted conditions. This study developed a physiologically based pharmacokinetic (PBPK) model utilizing published human data on the metabolic cascade of orally derived, low-concentration (placebo, 5 μg and 10 μg) supplementation of vitamin D over the course of 28 days in the absence of sunlight. Vitamin D and its metabolites are highly lipophilic and binding assays of these compounds in serum may not account for binding by lipids and additional proteins. To compensate for the additional bound amounts, this study allowed the effective adipose-plasma partition coefficient to vary dynamically with the concentration of each compound in serum utilizing the Hill equation for binding. Through incorporating the optimized parameters with the adipose partition coefficient adaptation to the PBPK model, this study was able to fit serum concentration data for circulating vitamin D at all three supplementation concentrations within confidence intervals of the data. Copyright © 2017 John Wiley & Sons, Ltd.

The Effect of Vitamin D3 Supplementation on Hepcidin, Iron, and IL-6 Responses after a 100 km Ultra-Marathon

“…This statistically significant drop was fast and large (from 27.13 ± 3.67 ng/mL to 20.41 ± 4.67 ng/mL). In contrast to the current study, Sawyer et al showed only a moderate decline of vitamin D level after four weeks [42]. On the other hand, Schoenmakers et al found in their mathematical model that the 25 (OH)D can also decrease fast [43].…”

Personalise vitamin D3 using physiologically based pharmacokinetic modelling

“…17 A published PBPK model hypothesized that a nonconstant partition coefficient could be used to fit short-term low dose 25(OH)D plasma profile. 16 Model Run010 explored this hypothesis but it overfitted the data (Table S7). Our model was simpler, provided good inference for all unknown parameters, and was well qualified for a variety of doses with a unique set of parameters.…”

“…Previously, a physiologically‐based pharmacokinetic (PBPK) model attempted to fit short duration (28 days) low dose (5 µg/d and 10 µg/d, 1 µg = 40 IU) 25(OH)D plasma data with 5 time points for each group. 16 The complex model had 34 parameters. The authors noticed a high degree of variability in the baseline serum 25(OH)D levels, but unfortunately did not assess the impact of subjects who were believed to be outliers (5 µg/d: 3/8.…”

“…Variability estimates would be expected to change if these outliers were accounted for. 16 A nonlinear mixed effects model was reported to have successfully recapitulated PK data for a range of doses. 17 However, population‐level predictions by that model could be improved, as predictions deviated from observations by about 50% in some cases.…”

Vitamin D Sources, Metabolism, and Deficiency: Available Compounds and Guidelines for Its Treatment

“…Because the pharmacokinetics of vitamin D is complex and depends on a number of determinants, new mathematical models have been proposed in the attempt to better predict the response to different existing compounds and also to new metabolites in development [ 62 , 64 ].…”