A Pharmacokinetic Bridging Study to Compare Systemic Exposure to Budesonide between Budesonide Oral Suspension and ENTOCORT EC in Healthy Individuals

Abstract

Background and objectives: Currently, there are no US FDA-approved therapies for eosinophilic esophagitis (EoE). Budesonide oral suspension (BOS; SHP621, TAK-721) is a viscous, muco-adherent, oral formulation of budesonide that is in phase III development for the treatment of EoE. BOS 2 mg twice daily was studied in 12- and 36-week phase III studies for the induction and maintenance of clinical remission in adults and adolescents with EoE (NCT02605837 and NCT02736409). ENTOCORT EC is a gelatin capsule formulation of budesonide that is FDA-approved for the treatment of mild-to-moderate active Crohn's disease (CD) in adults and children. This study compared the systemic exposure to budesonide from BOS with that from ENTOCORT EC, aiming to provide the pharmacokinetic (PK) bridge to the safety data of ENTOCORT EC.

Methods: Healthy adult volunteers (n = 22) were enrolled in an open-label, single-center, crossover study. Participants received a single oral dose of BOS 2 mg and a single oral dose of ENTOCORT EC 9 mg under fasting conditions in a randomized sequence, with a 48-h washout period between treatments. PK parameters were calculated by non-compartmental analysis and compared between treatments using a mixed-effects model with sequence and treatment as fixed effects and individuals within sequence as a random effect.

Results: Plasma budesonide concentrations showed that budesonide was absorbed significantly faster from BOS 2 mg than from ENTOCORT EC 9 mg, with peak concentrations reached at 1.5 and 4 h, respectively (p < 0.001). Systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that observed after a single oral dose of ENTOCORT EC 9 mg; the least squares geometric mean maximum plasma concentration and the area under the concentration-time curve from the time of dosing to infinity and from the time of dosing to the last measurable concentration of budesonide after BOS 2 mg were 71.1%, 33.5%, and 33.6% of those after ENTOCORT EC 9 mg, respectively. No notable differences in treatment-emergent adverse events were observed between individuals treated with either drug; all events were mild and none resulted in discontinuation from the study.

Conclusions: This study demonstrated that systemic exposure to budesonide after a single oral dose of BOS 2 mg was lower than that after a single oral dose of ENTOCORT EC 9 mg. These results provide PK bridging data to compare BOS with therapeutic doses of ENTOCORT EC with respect to safety information.

Fig. 1

Phase I crossover study design. Participants were randomly assigned to one of two treatment sequences, with a 48-h washout period between each treatment: BOS 2 mg (0.2 mg/mL in a volume of 10 mL) or ENTOCORT EC 9 mg (three 3-mg gelatin capsules) after a 10-h fasting period. Serial blood samples for determining plasma budesonide concentrations were collected in both treatment periods at predose and through 24 h postdose. BOS budesonide oral suspension

Fig. 2

Mean ± SD plasma concentrations of budesonide over time after a single dose of BOS 2 mg or ENTOCORT EC 9 mg on linear and semi-logarithmic scales. Plasma concentrations of budesonide peaked at approximately 1.5 h for BOS 2 mg and showed significantly faster absorption than ENTOCORT EC 9 mg, which peaked at approximately 4 h after dosing. BOS budesonide oral suspension, SD standard deviation