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

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 (<i>n</i> = 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.