Population Pharmacokinetics of Total and Protein-Unbound Prednisolone in Children with Immune-Mediated and Systemic Inflammatory Diseases

Abstract

BACKGROUND AND OBJECTIVE: High-dose systemic prednisolone is the mainstay treatment of 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 by substantial adverse effects in the majority of patients. 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 pharmacokinetics and determinants of variability of protein-bound and unbound prednisolone in children with (auto)immune diseases. METHODS: Patients received ≥ 0.5 mg/kg systemic prednisolone for either an autoimmune disease or as part of allogeneic haematopoietic cell transplantation (HCT). A priori allometric scaling was implemented, normalised to a body weight (BW) of 70 kg. RESULTS: The study population consisted of 60 children with a median (range) age of 10 (0.2-19) years and a BW of 36.5 (5.0-109) 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, and the circadian rhythm of CBG. The population estimates (95% confidence interval [CI]) for the binding affinity of prednisolone to albumin was 200 µM (164-253) and to CBG was 0.048 µM (0.043-0.053). The population estimate for clearance (95% CI) was 155 L/h (137-182). Patients with prednisolone as prophylaxis following HCT had a 10% higher clearance 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.