Population Pharmacokinetic Model of Vitamin D3 and Metabolites in Chronic Kidney Disease Patients with Vitamin D Insufficiency and Deficiency

Abstract

Vitamin D insufficiency and deficiency are highly prevalent in patients with chronic kidney disease (CKD), and their pharmacokinetics are not well described. The primary study objective was to develop a population pharmacokinetic model of oral cholecalciferol (VitD₃) and its three major metabolites, 25-hydroxyvitamin D₃ (25D₃), 1,25-dihydroxyvitamin D₃ (1,25D₃), and 24,25-dihydroxyvitamin D₃ (24,25D₃), in CKD patients with vitamin D insufficiency and deficiency. CKD subjects (n = 29) were administered one dose of oral VitD₃ (5000 I.U.), and nonlinear mixed effects modeling was used to describe the pharmacokinetics of VitD₃ and its metabolites. The simultaneous fit of a two-compartment model for VitD₃ and a one-compartment model for each metabolite represented the observed data. A proportional error model explained the residual variability for each compound. No assessed covariate significantly affected the pharmacokinetics of VitD₃ and metabolites. Visual predictive plots demonstrated the adequate fit of the pharmacokinetic data of VitD₃ and metabolites. This is the first reported population pharmacokinetic modeling of VitD₃ and metabolites and has the potential to inform targeted dose individualization strategies for therapy in the CKD population. Based on the simulation, doses of 600 International Unit (I.U.)/day to 1000 I.U./day for 6 months are recommended to obtain the target 25D₃ concentration of between 30 and 60 ng/mL. These simulation findings could potentially contribute to the development of personalized dosage regimens for vitamin D treatment in patients with CKD.

Keywords: cholecalciferol; chronic kidney disease; population pharmacokinetic model; vitamin D deficiency.

Figure 1

Schematic diagram of combined population pharmacokinetic model for vitamin D₃ (VitD₃), 25-hydroxyvitamin D₃ (25D₃), 1,25-dihydroxyvitamin D₃ (1,25D₃), and 24,25-dihydroxyvitamin D₃ (24,25D₃). Ka = absorption rate constant; k_endog = endogenous production rate constant; C0 = VitD₃ baseline concentration; Vc/F_VitD3 = apparent central volume of distribution of VitD₃; CL/F_VitD3 = apparent clearance of VitD₃; Vp/F_VitD3 = peripheral volume of distribution of VitD₃; Q/F_VitD3 = intercompartmental clearance of VitD₃; fm1 = fraction of VitD₃ metabolized to 25D₃; C0_m1 = 25D₃ baseline concentration; V_m1 = volume of distribution of 25D₃; CL_m1 = clearance of 25D₃; f_m2 = fraction of 25D₃ metabolized to 1,25D₃; C0_m2 = 1,25D₃ baseline concentration; V_m2 = volume of distribution of 1,25D₃; CL_m2 = clearance of 1,25D₃; C0_m3 = 24,25D₃ baseline concentration; V_m3 = volume of distribution of 24,25D₃; CL_m3 = clearance of 24,25D₃.

Figure 2

Goodness–of–fit plots, (A) OBS vs. IPRED, (B) OBS vs. PRED, (C) CWRES vs. PRED, and (D) CWRES vs. time for model-predicted (i) 25-hydroxyvitamin D₃ (25D₃) plasma concentrations, (ii) 1,25-dihydroxyvitamin D₃ (1,25D₃), (iii) 24,25-dihydroxyvitamin D₃, (24,25D₃), and (iv) vitamin D₃ (VitD₃). OBS = observed concentration; IPRED = individual predicted concentration; PRED = population predicted concentration; CWRES = conditional weighted residuals. The black solid line in (A,B) represents the line of unity. The blue solid line in CWRES plot represents trend line for linear regression and red solid line is used to observe the distribution trend of residuals.

Figure 2

Goodness–of–fit plots, (A) OBS vs. IPRED, (B) OBS vs. PRED, (C) CWRES vs. PRED, and (D) CWRES vs. time for model-predicted (i) 25-hydroxyvitamin D₃ (25D₃) plasma concentrations, (ii) 1,25-dihydroxyvitamin D₃ (1,25D₃), (iii) 24,25-dihydroxyvitamin D₃, (24,25D₃), and (iv) vitamin D₃ (VitD₃). OBS = observed concentration; IPRED = individual predicted concentration; PRED = population predicted concentration; CWRES = conditional weighted residuals. The black solid line in (A,B) represents the line of unity. The blue solid line in CWRES plot represents trend line for linear regression and red solid line is used to observe the distribution trend of residuals.

Figure 3

VVPCs for the final model. Observed concentrations (circle) and 5th (solid line), 50th (dashed line), and 95th (dotted line) percentiles from observed (red) and predicted (blue) data for (A) 25-hydroxyvitamin D₃ (25D₃), (B) 1,25-dihydroxyvitamin D₃ (1,25D₃), (C) 24,25-dihydroxyvitamin D₃ (24,25D₃), and (D) vitamin D₃ (VitD₃).

Figure 4

Population simulations for mean 25D₃ concentrations based on daily VitD₃ doses over six-month time period. (A) mean 25D₃ simulated concentration vs. time for dose of 600 I.U./day, (B) mean 25D₃ simulated concentration vs. time for dose of 1000 I.U./day, (C) mean 25D₃ simulated concentration vs. time for dose of 2000 I.U./day, (D) mean 25D₃ simulated concentration vs. time for dose of 5000 I.U./day, (E) mean 25D₃ simulated concentration vs. time for dose of 5000 I.U./day.