JE Möhlmann1,2, CA Lindemans3,4, MHA Jansen5, M van Luin1, AM Punt6, S Ezzafzafi1, S Nierkens3,7, ADR Huitema1,2,8, AHM de Vries Schultink1
1Department of Clinical Pharmacy, UMC Utrecht, 2Department of Pharmacology, Princess Máxima Centre for Paediatric Oncology, 3Princess Máxima Centre for Paediatric Oncology, 4Department of Paediatrics, Wilhelmina Children’s Hospital, UMC Utrecht, 5Department of Paediatric Rheumatology and Immunology, Wilhelmina’s Children’s Hospital, UMC Utrecht, 6Department of Clinical Diagnostics, UMC Utrecht, 7Center for Translational Immunology, UMC Utrecht, 8Department of Pharmacy and Pharmacology, Netherlands Cancer Institute
Introduction: High-dose systemic prednisolone is the mainstay treatment for children with various (auto)immune diseases. The standard empirical dosing regimen with dosages up to 2 mg/kg/day is generally adequate for immune suppression, though often accompanied with substantial adverse effects in the majority of patients.[1] Pharmacokinetic (PK) variability may be an important determinant for both efficacy and toxicity but has only limitedly been investigated in children. This research aimed to characterise the population PK and determinants of variability of protein-bound and unbound prednisolone in children with (auto)immune diseases. Methods: Two prospective studies were initiated for paediatric patients with an indication for systemic prednisolone. The PIKACHU study included patients undergoing a haematopoietic cell transplantation (HCT) and the CARPE DIEM study included patients with autoimmune and systemic inflammatory diseases. Patients received =0.5 mg/kg systemic prednisolone, either orally or intravenously. In the HCT cohort PK samples were collected pre-dose and at 0.5, 2, 4 and 7h (± 0.5 to 1h) post-prednisolone administration. In the autoimmune cohort PK samples were collected pre-dose and at 0.5, 2 and 4h (± 0.5 to 1h) post-prednisolone administration. For both cohorts, the total and the unbound prednisolone concentrations in serum were quantified by liquid chromatography-tandem mass spectrometry.[2] Concentrations corticosteroid binding globuline (CCBG) was measured in serum in every first collected sample of the PK-curve, using a radio immunoassay (DIAsource).[3] Various patients’ characteristics were obtained to evaluate covariate effects such as gender, age, bodyweight, pharmaceutical formulation (tablet or suspension) and administration via tube or not, concurrent medication with cyclosporin A, CYP-interactors, antithymocyte globulin, diagnosis-, cohort- and regimen-related variables and diagnosis with GvHD. Missing values for laboratory values were replaced by the covariate median. A population PK model was developed using NONMEM (v7.5.1.) Results: The study population consisted of 60 children with a median (range) age of 10 (0.2 to 19) years and a body weight of 36.5 (5.0 to 109) kg. A total of 305 serum samples from 68 PK occasions were measured for total and protein-unbound prednisolone concentrations. The PK data were best described by a two-compartment model, accounting for both the linear and saturable binding of prednisolone to albumin and corticosteroid binding globulin (CBG), respectively, where for CBG the circadian rhythm was taken into account using a previously developed model by Melin et al. [4]. The population estimates (95% confidence interval, CI) for the binding affinity of prednisolone to albumin and CBG were 200 (164 – 253) µM and 0.048 (0.043 – 0.053) µM, respectively. A priori allometric scaling of PK parameters was implemented, normalised to a body weight of 70 kg, and effectively captured the relationship with body size. The population estimate for CL (95% CI) was 155 (137 – 182) L/h. Patients with prednisolone as prophylaxis following HCT had a 10% higher CL compared with patients treated for graft-versus-host disease or an autoimmune disease. Conclusion: This population PK model provides valuable insights into PK variability of prednisolone and can be used to address the clinical implications of BW-based dosing of prednisolone in children with immune-mediated and inflammatory diseases.
[1] McDonough AK, Curtis JR, Saag KG. The epidemiology of glucocorticoid-associated adverse events. Curr Opin Rheumatol. 2008 Mar;20(2):131–7. [2] Möhlmann JE, van Luin M, Lentjes EGWM, Huitema ADR, Punt AM. Bioanalysis of protein-unbound prednisolone in serum using equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Dec 26;1252:124440. [3] DIAsource ImmunoAssays S.A. CBG-RIA-CT – KIP1809 – Instructions for use [Internet]. 2023 [cited 2025 Feb 4]. Available from: https://diasource.s3.eu-west-3.amazonaws.com/website/medias/2023/09/kip1809-650314b0b9916.pdf?1694700720 [4] Melin J, Hartung N, Parra-Guillen ZP, Whitaker MJ, Ross RJ, Kloft C. The circadian rhythm of corticosteroid-binding globulin has little impact on cortisol exposure after hydrocortisone dosing. Clin Endocrinol (Oxf). 2019 Jul;91(1):33–40.
Reference: PAGE 33 (2025) Abstr 11396 [www.page-meeting.org/?abstract=11396]
Poster: Drug/Disease Modelling - Paediatrics