TY - JOUR
T1 - Predicting budesonide performance in healthy subjects and patients with Crohn's disease using biorelevant in vitro dissolution testing and PBPK modeling
AU - Effinger, Angela
AU - O'Driscoll, Caitriona M.
AU - McAllister, Mark
AU - Fotaki, Nikoletta
N1 - Funding Information:
This work has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 674909 (PEARRL). Additionally, the authors would like to thank Certara for providing the license for the Simcyp? simulator.
Funding Information:
This work has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 674909 (PEARRL). Additionally, the authors would like to thank Certara for providing the license for the Simcyp® simulator.
Publisher Copyright:
© 2020
PY - 2021/2/1
Y1 - 2021/2/1
N2 - Objectives: Drug product performance might be affected in Crohn's disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data. The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data. Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.
AB - Objectives: Drug product performance might be affected in Crohn's disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data. The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data. Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.
KW - Absorption
KW - Bioavailability
KW - Inflammatory Bowel Disease
KW - Pharmacokinetic modeling
KW - Physiologically based pharmacokinetics
UR - http://www.scopus.com/inward/record.url?scp=85095571495&partnerID=8YFLogxK
U2 - 10.1016/j.ejps.2020.105617
DO - 10.1016/j.ejps.2020.105617
M3 - Article
AN - SCOPUS:85095571495
VL - 157
JO - European Journal of Pharmaceutical Sciences
JF - European Journal of Pharmaceutical Sciences
SN - 0928-0987
M1 - 105617
ER -