Dataset Information

Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling.

ABSTRACT: Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or coadministration of a P-glycoprotein inhibitor. Because the combined effects of drug-drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P-glycoprotein inhibitors is empirical at its best. We conducted virtual drug-drug interactions studies between DABE and the P-glycoprotein inhibitor verapamil in RI populations using physiologically based pharmacokinetic modeling. The developed physiologically based pharmacokinetic model for DABE and dabigatran was used to predict trough dabigatran concentrations in the presence and absence of verapamil in virtual RI populations. The population-based physiologically based pharmacokinetic model provided the most appropriate dosing regimen of DABE for likely clinical scenarios, such as drug-drug interactions in this RI population based on available knowledge of the systems changes and in the absence of actual clinical studies.

SUBMITTER: Doki K

PROVIDER: S-EPMC6389344 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling.

Doki Kosuke K Neuhoff Sibylle S Rostami-Hodjegan Amin A Homma Masato M

CPT: pharmacometrics & systems pharmacology 20190201 2

Plasma concentrations of dabigatran, an active principle of prodrug dabigatran etexilate (DABE), are increased by renal impairment (RI) or coadministration of a P-glycoprotein inhibitor. Because the combined effects of drug-drug interactions and RI have not been evaluated by means of clinical studies, the decision of DABE dosing for RI patients receiving P-glycoprotein inhibitors is empirical at its best. We conducted virtual drug-drug interactions studies between DABE and the P-glycoprotein inh ...[more]

PMID: 30659778

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Project description:BACKGROUND:Application of idarucizumab and hemodialysis are options to reverse the action of the oral anticoagulant dabigatran in emergency situations. OBJECTIVES:The objectives of this study were to build and evaluate a mechanistic, whole-body physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model of idarucizumab, including its effects on dabigatran plasma concentrations and blood coagulation, in healthy and renally impaired individuals, and to include the effect of hemodialysis on dabigatran exposure. METHODS:The idarucizumab model was built with the software packages PK-Sim® and MoBi® and evaluated using the full range of available clinical data. The default kidney structure in MoBi® was extended to mechanistically describe the renal reabsorption of idarucizumab and to correctly reproduce the reported fractions excreted into urine. To model the PD effects of idarucizumab on dabigatran plasma concentrations, and consequently also on blood coagulation, idarucizumab-dabigatran binding was implemented and a previously established PBPK model of dabigatran was expanded to a PBPK/PD model. The effect of hemodialysis on dabigatran was implemented by the addition of an extracorporeal dialyzer compartment with a clearance process governed by dialysate and blood flow rates. RESULTS:The established idarucizumab-dabigatran-hemodialysis PBPK/PD model shows a good descriptive and predictive performance. To capture the clinical data of patients with renal impairment, both glomerular filtration and tubular reabsorption were modeled as functions of the individual creatinine clearance. CONCLUSIONS:A comprehensive and mechanistic PBPK/PD model to study dabigatran reversal has been established, which includes whole-body PBPK modeling of idarucizumab, the idarucizumab-dabigatran interaction, dabigatran hemodialysis, the pharmacodynamic effect of dabigatran on blood coagulation, and the impact of renal function in these different scenarios. The model was applied to explore different reversal scenarios for dabigatran therapy.

Dataset Information

Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling.

Publications

Assessing Potential Drug-Drug Interactions Between Dabigatran Etexilate and a P-Glycoprotein Inhibitor in Renal Impairment Populations Using Physiologically Based Pharmacokinetic Modeling.

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