Determination of optimal vitamin D₃ dosing regimens in HIV‐infected paediatric patients using a population pharmacokinetic approach

Abstract

AIMSTo investigate D] population pharmacokinetics in children and adolescents, to establish factors that influence 25(OH)D pharmacokinetics and to assess different vitamin D3 dosing schemes to reach sufficient 25(OH)D concentrations (>30 ng ml −1 ). METHODSThis monocentric prospective study included 91 young HIV-infected patients aged 3 to 24 years. Patients received a 100 000 IU vitamin D3 supplementation. A total of 171 25(OH)D concentrations were used to perform a population pharmacokinetic analysis. RESULTSAt baseline 28% of patients had 25(OH)D concentrations below 10 ng ml −1 , 69% between 10 and 30 ng ml −1 and 3% above 30 ng ml −1 . 25(OH)D pharmacokinetics were best described by a one compartment model with an additional production parameter reflecting the input from diet and sun exposure. The effects of skin phototype and bodyweight were significant on 25(OH)D production before any supplementation. The basal level was 27% lower in non-white skin phototype patients and was slightly decreased with bodyweight. No significant differences in 25(OH)D concentrations were related to antiretroviral drugs. To obtain concentrations between 30 and 80 ng ml −1 , patients with baseline concentrations between 10 and 30 ng ml −1 should receive 100 000 IU per 3 months. However, vitamin D deficient patients (<10 ng ml −1 ) would need an intensive phase of 100 000 IU per 2 weeks (two times) followed 2 weeks later by a maintenance phase of 100 000 IU per 3 months. CONCLUSIONSSkin phototype and bodyweight had an influence on the basal production of 25(OH)D. According to 25(OH)D baseline concentrations, dosing schemes to reach sufficient concentrations are proposed.

Population pharmacokinetics and dose optimisation of colecalciferol in paediatric patients with chronic kidney disease

“…In our study, a notable difference with previous studies is the large between-subject variability in 25(OH)D clearance. Compared to other studies which have also reported high between-subject variability (60-65%) despite a relatively homogeneous population, [19][20][21] our finding of 94% is likely to reflect an even more heterogenous cohort of patients with respect to 25(OH)D clearance. Although no covariate was identified as significant in our study, there is a strong biological plausibility that clearance could be affected in subjects with primary glomerular disease; our cohort included 20 children with glomerular disease, who compared to those with nonglomerular disease, required clearance may differ by race.…”

“…We have developed the first population PK model of oral colecalciferol using data from an randomised controlled trial in children The high volume of distribution estimate in our study is perhaps to be expected given colecalciferol and 25(OH)D are both lipophilic molecules, but our estimated value is higher than those reported by Foissac et al and in other adult studies. [19][20][21] The differences in volume of distribution may be explained by differences in body composition of the study populations and/or differences in 25(OH)D protein binding. We acknowledge that there were insufficient data in our study to fully quantify a 2-compartment model that may better describe the tissue distribution of colecalciferol and 25(OH)D. Earlier studies, although limited, have pointed to a biphasic distribution, [35][36][37] and a 2-compartment population PK model of colecalciferol has been described in only 1 meta-analysis consisting of >5000 adult subjects.…”

The impact of vitamin D supplementation on musculoskeletal health outcomes in children, adolescents, and young adults living with HIV: A systematic review

“…With the exception of one Hepatitis C co-infected individual in the Foissac et al . [ 69 ] study, participants had no concomitant acute and/or chronic disease, apart from HIV. There were no patients noted to have concurrent TB.…”

“…Higher mean monthly 25OHD values were seen with higher doses of cholecalciferol [ 55 ]. Lower baseline values of 25OHD negatively impacted final serum 25OHD concentrations, and extended the time needed to reach 25OHD >50 nmol/L and 75 nmol/L [ 66 , 69 ]. Without supplementation, dietary intake of cholecalciferol, noted to be between 90–425 IU/day, was insufficient in achieving 25OHD >75 nmol/L.…”

“…This dose may be simplified to 1,500–2,000 IU/day for all paediatric patients, a recommendation which aligns with optimal dose modelling data by Foissac et al . [ 82 ]. Higher doses are likely to be required for treatment of documented vitamin D deficiency, and if used, the full safety profile should be substantiated under medical supervision.…”