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• W3178532084 endingPage "105932" @default.
• W3178532084 startingPage "105932" @default.
• W3178532084 abstract "Dabigatran etexilate (DABE) has been suggested as a clinical probe for intestinal P-glycoprotein (P-gp)-mediated drug-drug interaction (DDI) studies and, as an alternative to digoxin. Clinical DDI data with various P-gp inhibitors demonstrated a dose-dependent inhibition of P-gp with DABE. The aims of this study were to develop a joint DABE (prodrug)-dabigatran reduced physiologically-based-pharmacokinetic (PBPK) model and to evaluate its ability to predict differences in P-gp DDI magnitude between a microdose and a therapeutic dose of DABE. A joint DABE-dabigatran PBPK model was developed with a mechanistic intestinal model accounting for the regional P-gp distribution in the gastrointestinal tract. Model input parameters were estimated using DABE and dabigatran pharmacokinetic (PK) clinical data obtained after administration of DABE alone or with a strong P-gp inhibitor, itraconazole, and over a wide range of DABE doses (from 375 µg to 400 mg). Subsequently, the model was used to predict extent of DDI with additional P-gp inhibitors and with different DABE doses. The reduced DABE-dabigatran PBPK model successfully described plasma concentrations of both prodrug and metabolite following administration of DABE at different dose levels and when co-administered with itraconazole. The model was able to capture the dose dependency in P-gp mediated DDI. Predicted magnitude of itraconazole P-gp DDI was higher at the 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) ) compared to the therapeutic dose (predicted median fold-increase in AUC+inh/AUCcontrol = 3.48 (2.37–4.84) ). In addition, the reduced DABE-dabigatran PBPK model predicted successfully the extent of DDI with verapamil and clarithromycin as P-gp inhibitors. Model-based simulations of dose staggering predicted the maximum inhibition of P-gp when DABE microdose was concomitantly administered with itraconazole solution; simulations also highlighted dosing intervals required to minimise the DDI risk depending on the DABE dose administered (microdose vs. therapeutic). This study provides a modelling framework for the evaluation of P-gp inhibitory potential of new molecular entities using DABE as a clinical probe. Simulations of dose staggering and regional differences in the extent of intestinal P-gp inhibition for DABE microdose and therapeutic dose provide model-based guidance for design of prospective clinical P-gp DDI studies." @default.
• W3178532084 created "2021-07-19" @default.
• W3178532084 creator A5039851568 @default.
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• W3178532084 creator A5059236152 @default.
• W3178532084 creator A5078216165 @default.
• W3178532084 date "2021-10-01" @default.
• W3178532084 modified "2023-10-10" @default.
• W3178532084 title "Reduced physiologically-based pharmacokinetic model of dabigatran etexilate-dabigatran and its application for prediction of intestinal P-gp-mediated drug-drug interactions" @default.
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• W3178532084 doi "https://doi.org/10.1016/j.ejps.2021.105932" @default.
• W3178532084 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34260894" @default.
• W3178532084 hasPublicationYear "2021" @default.
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