Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia

Abstract

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

Keywords: LC-MS/MS; eosinophilic oesophagitis (EoE); oesophageal atresia (EA); oral viscous budesonide; pharmacokinetics; population pharmacokinetic modelling; systemic absorption.

Figure 1

Observed budesonide plasma concentrations over time in patients treated with twice daily doses of 0.8 mg (blue dots) or 1.0 mg (red dots) oral viscous budesonide.

Figure 2

Schematic representation of the structural pharmacokinetic model. Parallel zero-order and first-order absorption processes with first-order elimination. Two different absorption processes take place following oral administration of budesonide. Initially, a fraction of the dose (F2) is absorbed in the oesophagus by zero-order kinetics, which progresses over a given period of time (D2), following a lag time (ALAG2). The remaining fraction of the dose (F1 = 1 − F2) is absorbed elsewhere in the gastrointestinal tract by first-order kinetics, characterised by the absorption rate constant Ka. Absorbed budesonide equilibrates in a central (V2) and a peripheral (V3) compartment according to an intercompartmental clearance (Q). Elimination from the central compartment (V2) occurs through a first-order process (CL).