Jennifer Lang (1), Ludwig Vincent (2), Marylore Chenel (3), Kayode Ogungbenro (1), Aleksandra Galetin (1)
(1) Centre for Applied Pharmacokinetic Research, University of Manchester, UK; (2) Technologie Servier, France; (3) Institut de Recherches Internationales Servier, France
Background: New recommendations from regulatory authorities have suggested dabigatran etexilate (DABE) as a clinical probe for intestinal P-gp-mediated drug-drug interaction (DDI) studies instead of the commonly used digoxin due to its higher sensitivity and specificity [1]. Clinical DDI data with several P-gp inhibitors have demonstrated dose-dependent extent of interaction with DABE, suggesting saturation of P-gp at high dose levels [2]. Previous modelling efforts have focused on P-gp DDI with DABE therapeutic dose with no consideration of microdose DDI data and non-linearity in P-gp DDI with this clinical probe. Therefore, P-gp transport kinetics may not have been appropriately characterised. The aims of this study were (i) to develop a reduced joint PBPK model for DABE (prodrug) and dabigatran (active metabolite) and (ii) to investigate the potential of the model to predict dose-dependent P-gp DDI risk between DABE microdose and therapeutic dose.
Methods: A reduced DABE-dabigatran PBPK model was developed by implementing a mechanistic intestinal model, which accounted for P-gp regional differences in expression in the gut. Prior input parameters were taken from in vitro and literature data. Certain input parameters were optimised using DABE and dabigatran pharmacokinetic (PK) data from intravenous and oral clinical studies (DABE dose range = 375 µg to 400 mg) as well as clinical DDI data with DABE microdose (375 µg) co-administered with itraconazole (strong P-gp inhibitor). Subsequently, the model was verified against several data from clinical DDI studies with additional P-gp inhibitors co-administered with various DABE doses.
Results: DABE-dabigatran PBPK model satisfactorily described DABE and dabigatran plasma concentrations following administration of DABE at different doses and dose schedules and dose, alone and when co-administered with itraconazole. Magnitude of itraconazole-P-gp DDI was higher at DABE microdose (predicted vs observed median fold-increase in AUC+inh/AUCcontrol (min-max) = 5.88 (4.29-7.93) vs 6.92 (4.96-9.66) ng.h/mL) compared to the therapeutic dose (predicted median fold-increase in AUC+inh/AUCcontrol = 3.48 (2.37-4.84) ng.h/mL). The model was then used for prospective prediction of intestinal P-gp DDI with other P-gp inhibitors (verapamil and clarithromycin) and it successfully captured the observed dose dependent DDI. Simulations of dose staggering maximum extent of P-gp mediated DDI with concomitant administration of itraconazole, regardless of DABE dose.
Conclusions: The DABE-dabigatran PBPK model developed herein can be used as part of modelling framework for the evaluation of P-gp inhibitory potential of new molecular entities using DABE as a clinical probe and the design of prospective clinical P-gp DDI studies. In addition, this model can be used for various other purposes such as investigation of the maximum and minimum DDI risks through simulation of dose staggering but also the exploration of intestinal regional differences in the extent of intestinal P-gp inhibition for DABE microdose and therapeutic dose.
References:
[1] Chu et al., Clinical Pharmacology & Therapeutics 104 (2018) 788–792.
[2] Prueksaritanont et al., Clinical Pharmacology & Therapeutics 101 (2016) 519–530.
Reference: PAGE 29 (2021) Abstr 9730 [www.page-meeting.org/?abstract=9730]
Poster: Drug/Disease Modelling - Absorption & PBPK