Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK.
Administration, Oral
Aged
Aged, 80 and over
Biological Availability
Computer Simulation
Cross-Over Studies
Fasting
Female
Food-Drug Interactions
Gastric Emptying
Healthy Volunteers
Humans
Intestinal Absorption
Male
Models, Biological
Piperidines
/ administration & dosage
Proton Pump Inhibitors
/ administration & dosage
Sulfones
/ administration & dosage
Tablets
PBPK modelling
biorelevant dissolution
clinical study
negative food effect
proton pump inhibitor
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
29 Oct 2020
29 Oct 2020
Historique:
received:
28
02
2020
accepted:
07
10
2020
entrez:
30
10
2020
pubmed:
31
10
2020
medline:
7
8
2021
Statut:
epublish
Résumé
To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution. Compendial dissolution using a paddle method and TIM-1 biorelevant dissolution were performed and incorporated into a previously reported PBPK model. A two-part clinical study evaluated tablet formulations in the fasted/fed (high fat) state (Part A), and the impact of food (fasted/normal/high fat) and Proton Pump Inhibitor (PPI) co-administration for a selected formulation; as well as a formulation containing DNX HBr in the monohydrate state (Part B). TIM-1 data showed that the fed state bioaccessibility of DNX was significantly decreased compared to the fasted state with no significant differences between formulations. Dosed with normal/high fat food the selected formulation showed comparable exposure and a modest increase in DNX systemic PK was observed with PPI dependent on meal type. Under fed conditions DNX systemic exposure was comparable for the monohydrate and hemihydrate formulations. The integration of biorelevant TIM-1 data into the PBPK model led to the successful simulation of a DNX negative food effect. Interactions between DNX and food components are the likely the source of the negative food effect via micellar entrapment, ion pairing and/or meal induced viscosity changes.
Identifiants
pubmed: 33123802
doi: 10.1007/s11095-020-02948-z
pii: 10.1007/s11095-020-02948-z
doi:
Substances chimiques
Piperidines
0
Proton Pump Inhibitors
0
Sulfones
0
Tablets
0
danirixin
R318PGH5VP
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
233Références
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