Abstract
AimsThe prevalence of vitamin D deficiency is high in children with chronic kidney disease (CKD). However, current dosing recommendations are based on limited pharmacokinetic (PK) data. This study aimed to develop a population PK model of colecalciferol that can be used to optimise colecalciferol dosing in this population.MethodsData from 83 children with CKD were used to develop a population PK model using a nonlinear mixed effects modelling approach. Serum creatinine and type of kidney disease (glomerular vs. nonglomerular disease) were investigated as covariates, and optimal dosing was determined based on achieving and maintaining 25‐hydroxyvitamin D (25(OH)D) concentration of 30–48 ng/mL.ResultsThe time course of 25(OH)D concentrations was best described by a 1‐compartment model with the addition of a basal concentration parameter to reflect endogenous 25(OH)D production from diet and sun exposure. Colecalciferol showed wide between‐subject variability in its PK, with total body weight scaled allometrically the only covariate included in the model. Model‐based simulations showed that current dosing recommendations for colecalciferol can be optimised using a weight‐based dosing strategy.ConclusionThis is the first study to describe the population PK of colecalciferol in children with CKD. PK model informed dosing is expected to improve the attainment of target 25(OH)D concentrations, while minimising the risk of overdosing.
Highlights
Vitamin D deficiency is widely prevalent in patients with chronic kidney disease (CKD), and contributes to abnormalities in calcium, phosphate and parathyroid hormone homeostasis with increasing recognition of its key role in the pathogenesis of CKD–mineral and bone disorder.[1,2,3]
The Colecalciferol Supplementation in Children with Chronic Kidney Disease trial (C3 trial) was a prospective open-label, multicentre, randomised controlled trial to test the efficacy of 3 different dosing regimens of colecalciferol for 12 months in children with CKD.[16,17]. These data were used to develop a population PK model to allow better understanding of colecalciferol PK, and through PK simulation, we propose dosing recommendations for achieving and maintaining 25(OH)D concentrations between 30–48 ng/mL in children with CKD
These results provide an evidence-based approach for colecalciferol dose optimisation in children with CKD
Summary
Vitamin D deficiency is widely prevalent in patients with chronic kidney disease (CKD), and contributes to abnormalities in calcium, phosphate and parathyroid hormone homeostasis with increasing recognition of its key role in the pathogenesis of CKD–mineral and bone disorder.[1,2,3] International clinical practice guidelines provide consensus support for determining vitamin D status and correction of deficiency through vitamin D supplementation.[3,4]. Circulating total 25-hydroxyvitamin D (25(OH)D) is used clinically to assess an individual's vitamin D status It reflects vitamin D supply from cutaneous biosynthesis and exogenous intake, and is not under any negative feedback control.[5,6,7] Current CKD guidelines recommend initiation of vitamin D supplementation as for the general population,[4,6] with some expert panels recommending a target 25(OH)D concentration of at least 30 ng/mL.[3,8] Vitamin D supplementation is not without risks. While symptomatic vitamin D toxicity has been defined at 25(OH)D concentrations >100 ng/mL,[3] population based cohort studies have suggested an association between increased mortality and 25(OH)D concentrations >48 ng/ mL.[9,10] A more cautious supplementation approach is adopted in children with reduced renal reserve including those with CKD.[3]
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