Predicting budesonide performance in healthy subjects and patients with Crohn's disease using biorelevant in vitro dissolution testing and PBPK modeling

Understanding Discordance between In Vitro Dissolution, Local Gut and Systemic Bioequivalence of Budesonide in Healthy and Crohn’s Disease Patients through PBPK Modeling

“…Budesonide is a moderately lipophilic (logP o:w 2.62) neutral small molecule compound. Physicochemical and binding data were collected from Effinger’s paper [ 22 ]. The plasma protein binding was assigned to HSA and the K D was calculated by Simcyp.…”

“…The dissolution profile for Entocort ® EC was collected from reference [ 22 ] and used as the dissolution behavior of budesonide pellets. As the dissolution percentage in the experiment did not reach 100% at the last incubation time point, 100% dissolution was assumed at 12 h. Then, the dissolution profile was modified manually by adjusting the % release or altering the trigger pH to generate dissolution profiles for eight virtual formulations.…”

Clinical translation of advanced colonic drug delivery technologies

“…Moreover, GI disease can affect colonic physiology and function, and in turn affect drug behaviour and performance in patients [40][41][42][43][44]. For example, colonic pH is known to be reduced in IBD patients; changes to the epithelium and its transporters occur in colorectal cancer; and numerous diseases alter colonic transit time [9,45,46].…”

“…In addition, patients with IBD display up to 20% longer small intestinal transit times [48], differing fluid volumes with constipation and/or diarrhoea, a higher colonic epithelial permeability [49], colonic inflammation [50] and reduced surface mucus [51]. An increasing body of research has reported that systemic diseases indirectly related to the GI tract such as cystic fibrosis, Parkinson's disease, diabetes mellitus, human immunodeficiency virus (HIV) and chronic pain can also influence gut function [40][41][42][43][44].…”

Potential and Challenges in Application of Physiologically Based Pharmacokinetic Modeling in Predicting Diarrheal Disease Impact on Oral Drug Pharmacokinetics

“…chose budesonide as a model drug and constructed a PBPK model for a controlledrelease budesonide formulation. The PBPK model incorporated drug release data collected with in vitro studies conducted under conditions reflecting CD(Effinger et al, 2021). To examine the impact of CD on the release of budesonide from the Entocort® formulation, the controlled-release formulation used in Effinger et al's study, biorelevant media representative of healthy and CD conditions accounting for differences in bile salt/lecithin concentration, stomach pH, colonic osmolality for both fasted and fed states were developed.…”