Thesis defense Julia Möhlmann

All promotions can be followed live via this link: 
​https://www.uu.nl/en/organisation/utrecht-university-hall/schedule

This thesis focused on treatment refinement and enhancing the use of gold-standard immunosuppressive therapies in children with immune diseases and in paediatric haematopoietic cell transplantation (HCT).

Chapter 1 gave an overview of the current evidence on the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of systemic corticosteroids in paediatric and adult patients with autoimmune and inflammatory diseases. Evidence for a PK-efficacy relationship was inconclusive and limited, but there was some evidence for PK-toxicity relationship regarding the severity of Cushingoid features. This overview revealed the existing knowledge gap and that prospective research is still highly needed.

Chapter 2 described the development and validation of a liquid chromatography–tandem mass spectrometry (LC-MS/MS) assay for the quantification of prednisolone serum concentrations in patient samples. Protein-unbound prednisolone was obtained with equilibrium dialysis. Prednisolone protein binding showed no significant degradation after 30 months of storage at -80°C and was not influenced by multiple cycles of freezing and thawing.

Chapter 3 described the two-compartment population PK model of total and unbound prednisolone. The model included the linear and saturable binding of prednisolone to albumin and corticosteroid binding globulin (CBG), respectively, and the circadian rhythm of CBG. Allometric scaling of prednisolone PK adequately described the relationship with body size. It was recommended to address the clinical implications of the current BW-based dosing regimen in future PK-PD studies, as younger children are relatively underdosed.

In chapter 4 (interim analysis), the associations between prednisolone PK and presence of corticosteroid-related neuropsychiatric adverse effects (AEs) were explored in children with immune diseases, in addition to the development of behavioural changes over time and the perceptional differences in AEs between patients and their parents. There was a substantial presence of neuropsychiatric AEs, although the current analysis did not demonstrate associations with the PK of prednisolone.

In chapter 5 (interim analysis), the associations between prednisolone PK and the response to prednisolone as either prophylactic treatment or therapy of graft-versus-host disease (GvHD) in children post-HCT were explored. High variability in prednisolone exposure was observed, and a trend towards a lower exposure in patients diagnosed with GvHD. These patients tended to have a lower age, and consequently a lower BW. It was recommended to consider a different allometric-based dosing strategy in younger children, such as body surface area (BSA)-based dosing.

In chapter 6, the adherence to low-dose methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA) was addressed. With an ultrasensitive LC-MS/MS assay, plasma samples from JIA patients were analysed to assess adherence to MTX. Adherence in this JIA population was 88% shortly after initiation of MTX therapy and decreased to 77% after one year of treatment. Teenagers were more at risk for non-adherence.

Chapter 7 revealed the relative overdosing of fludarabine in young children undergoing HCT. Overexposure to fludarabine was observed in 50% to 80% of infant HCT patient, indicating that the BSA-based dosing strategy may be inappropriate in infants and young children and dose reductions in children <1 year of age could improve achievement of a fludarabine exposure within the optimal target range.