Negative Food Effect of Danirixin: Use of PBPK Modelling to Explore the Effect of Formulation and Meal Type on Clinical PK

Authors: Lloyd RS, Hingle MI, Bloomer JC, Charles SJ, Butler JM, Paul A, Zhu X, Miller B, D’Amico D, Donald A, Tal-Singer R, Ambery C
Publication: Pharm Res
Keywords: biopredictive dissolution, clinical formulation, fed state, gastroplus, mechanistic absorption model, pbbm, PBPK modeling, physiologically based biopharmaceutics model
Software: ADMET Predictor®, GastroPlus®

Abstract

Purpose
To use physiologically-based pharmacokinetic (PBPK) modelling to explore the food effect of different DNX hydrobromide (HBr) hemihydrate salt tablet formulations using biorelevant dissolution.

Methods
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).

Results
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.

Conclusions
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.

By Richard S. Lloyd, Martin I. Hingle, Jackie C. Bloomer, Stephen J. Charles, James M. Butler, Alan Paul, Xiaofeng Zhu, Bruce Miller, Donald D’Amico, Alison Donald, Ruth Tal-Singer & Claire Ambery