Ivy H. Song, PhD1, Trudy Rodgers, PhD2, Siobhán Hayes, PhD2, Colm Farrell, PhD2; 1Shire, a Takeda company, Lexington, MA; 2ICON Clinical Research, Marlow, England, United Kingdom
Introduction: A population pharmacokinetic (PK) model was developed for budesonide oral suspension (BOS), a topical corticosteroid designed for patients with eosinophilic esophagitis (EoE), to predict PK exposure and variability in adolescents (11–17 years old) and adults (≥18 years old) with EoE at a clinical dose of 2.0 mg twice daily (b.i.d.). Methods: Data were pooled from completed clinical trials of BOS: phase 1 (SHP621-101; healthy adults who received single doses of BOS 2.0 mg [various formulations, including A and B]), phase 2 (MPI 101-01 [NCT00762073]; patients with EoE 2–18 years old; BOS 0.35–2.0 mg once daily [q.d.] or b.i.d. [formulation A]) and phase 3 (SHP621-301 [NCT02605837]; patients with EoE 11–55 years old; BOS 2.0 mg b.i.d. [formulation B]). A population PK model was developed to describe the time course of plasma budesonide concentrations after BOS administration to healthy adults and patients with EoE using NONMEM (v7.3.0/v7.4.3). The covariates included: age, body weight, height, body surface area, sex, race, ethnicity, BOS dose and formulation, health status (healthy or EoE) and liver function markers (aspartate and alanine transaminases [AST and ALT]). The final model was used to predict steady-state exposure to budesonide following BOS 2.0 mg b.i.d. in adolescents and adults with EoE. Results: Data from 132 individuals (SHP621-101, n=22; MPI 101-01, n=38; and SHP621-301 adults, n=72) comprising 2144 concentration records were analyzed. The final population PK model is shown in Table 1. Body weight and BOS formulation were identified as significant covariates of budesonide PK. Apparent volume of distribution of the central compartment (Vc/F) increased with body weight. Absorption lag time was 15% shorter and relative bioavailability was 13% lower for formulation A versus formulation B. Age, sex, BOS dose, health status, AST and ALT were not predictors of budesonide PK. There were insufficient data to evaluate the effect of race. Steady-state exposure to budesonide following BOS 2.0 mg b.i.d. was predicted to be comparable between adolescents and adults with EoE. Discussion: Body weight and BOS formulation were identified as significant covariates of budesonide PK. No other predictors of budesonide PK were identified; dose of BOS was not identified as a covariate, indicating that the PK of budesonide was dose proportional. The final model predicted that steady-state exposure to budesonide after BOS 2.0 mg b.i.d. was comparable between adolescents and adults with EoE.
Table 1. Parameter estimates for the final population PK model.
Disclosures: Ivy Song: Shire, a Takeda Company – Employee. Takeda – Stockholder/Ownership Interest (excluding diversified mutual funds). Trudy Rodgers: ICON Clinical Research – Employee. Shire, a Takeda Company – Grant/Research Support. Siobhán Hayes: ICON Clinical Research – Employee. Shire, a Takeda Company – Grant/Research Support. Colm Farrell: ICON Clinical Research – Employee. Shire, a Takeda Company – Grant/Research Support.