Pharmacokinetics and pharmacodynamics of corticosteroids in paediatric patients with autoimmune and autoinflammatory diseases

The prevalence and incidence of autoimmune and autoinflammatory diseases have been increasing in the past few years. One of the biggest concerns in paediatric patients with systemic autoimmune and autoinflammatory diseases remains the high prevalence of toxicity due to the long-term treatment with systemic corticosteroids. The standard-of-care treatment of the majority of onset autoimmune disorders in paediatric patients is high dose systemic corticosteroids. While systemic corticosteroids have shown to be highly effective in the treatment of autoimmune and autoinflammatory diseases, the occurrence and severity of adverse events (AE) in patients treated with systemic corticosteroids is substantial. Toxicity is often severe but highly variable between patients and includes psychiatric and metabolic AE i.e., depression, personality and behavioural changes, sleep disturbances, excessive weight gain, hypertension, diabetes mellitus, growth retardation and cushingoid features. The association of pharmacokinetics (PK) of prednisolone and (level of) toxicity has not yet been investigated in children. University Medical Center (UMC) Utrecht has the unique facility of Liquid Chromatography-Mass Spectrometry (LC-MS) which enables to measure PK in an extremely precise manner. We hypothesize that precise dosing of corticosteroids, with optimal exposure in every individual patient, will decrease the incidence of AE in paediatric patients with autoimmune and autoinflammatory diseases. Therefore, we aim to investigate the PK in relation to toxicity (pharmacodynamics (PD)) of corticosteroids in children with autoimmune and autoinflammatory diseases.

To assess the PK/PD relationship of prednisolone regarding toxicity as clinical outcome in paediatric patients with autoimmune or autoinflammatory diseases

Prospective observational study

Primary: To assess the association between exposure (PK) and prednisolone toxicity (PD) in paediatric patients with autoimmune or autoinflammatory diseases

Secondary: To assess information about occurrence and grade of toxicity in paediatric patients with autoimmune or autoinflammatory diseasesand to identify determinants and its associated variability for development of a population PK model

Patients will not have direct benefit from participating in this study. The data obtained in this study will be used to assess the population PK and PD of prednisolone in children with onset autoimmune and autoinflammatory diseases. Burden will be minimal since for PK 4 (additional to standard of care) blood samples of 2 ml will be drawn (limited sampling strategy). The volume of blood that is drawn for the study does not exceed the recommended maximum. The applied sampling strategy is minimally invasive, since all the patients that are included are present during a routine outpatient clinic visit and will get a peripheral cannula for the purpose of routine sampling and PK-sampling, therefore there will be no extra blood punctures. Patients will be asked to stay 4-5 hours for the PK-sampling and to fill in a questionnaire about experiencing mental health AE.