Physiologically Based Pharmacokinetic Modeling of Vitamin D₃ and Metabolites in Vitamin D–Insufficient Patients

Abstract

A physiologically based pharmacokinetic (PBPK) model of vitamin D 3 and metabolites [25(OH)D 3 , 1,25(OH) 2 D 3 , and 24,25(OH) 2 D 3 ] is presented. In this study, patients with 25(OH)D 3 plasma concentrations below 30 ng/ml were studied after a single dose of 5,000 I.U. (125 µg) cholecalciferol, provided with 5,000 I.U. daily cholecalciferol supplementation until vitamin D replete (25(OH)D 3 plasma concentrations above 30 ng/ml), and had serial plasma samples were collected at each phase for 14 days. Total concentrations of vitamin D 3 and metabolites were measured by ultra-high performance liquid chromatography tandem mass spectrometry. A ninecompartment PBPK model was built using MATLAB to represent the triphasic study nature (insufficient, replenishing, sufficient). Stimulatory and inhibitory effect of 1,25(OH) 2 D 3 were incorporated by fold-changes in the primary metabolic enzymes CYP27B1 and CYP24A1, respectively. Incorporation of dynamic adipose partition coefficients for vitamin D 3 and 25(OH)D 3 and variable enzymatic reactions aided in model fitting.Measures of model predictions agreed well with data from metabolites, with 97%, 88%, and 98% of the data for 25(OH)D 3 , 24,25(OH) 2 D 3 , and 1,25(OH) 2 D 3 , respectively, within 2-fold of unity (fold error values between 0.5 and 2.0). Bootstrapping was performed and optimized parameters were reported with 95% confidence intervals.This PBPK model could be a useful tool for understanding the connections between vitamin D and its metabolites under a variety of clinical situations.

Vitamin D levels in the pre- and post-COVID-19 pandemic periods in pediatric patients with chronic kidney disease

“…In pediatric patients with CKD, its prevalence has reached 62.5 to >80% (16, 17), similar to our study finding prior to the start of the pandemic (76.6%). Different tissues unrelated to calcium and phosphorus metabolism express VDR and 1 alpha-hydroxylase (CYP27B1), which regulates gene expression in various tissues (18). Hence, VD is important in extraskeletal tissues as well as at the immunological, metabolic, and cardiovascular levels, among other systems (19, 20).…”