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.

Drug–Drug Interactions with Direct Oral Anticoagulants

“…A combination of increased absorption and reduced elimination can also lead to increased DOAC exposure that has previously not been investigated. A physiologically based pharmacokinetic model calculated that dabigatran C min will significantly increase in patients with moderate renal impairment who concomitantly take the P-gp inhibitor verapamil [72]. Despite the statement in the product label that only recommends a dose reduction to 110 mg twice daily, the authors suggested that the significantly increased C min values might be preventable by reducing dabigatran doses further to 75 mg twice daily [72].…”

“…A physiologically based pharmacokinetic model calculated that dabigatran C min will significantly increase in patients with moderate renal impairment who concomitantly take the P-gp inhibitor verapamil [72]. Despite the statement in the product label that only recommends a dose reduction to 110 mg twice daily, the authors suggested that the significantly increased C min values might be preventable by reducing dabigatran doses further to 75 mg twice daily [72]. However, as long as clinical trials investigating pharmacokinetics and clinical effects of this complex clinical situation are missing, it will be unclear whether patients treated with 110 mg twice daily are at an increased risk of bleeding and what dabigatran efficacy will be if doses are further reduced.…”

Role of direct oral anticoagulants in patients with kidney disease

“…Particular care should be taken in the CKD setting where the combination of reduced renal clearance and coadministration of P-glycoprotein inhibitors may increase bleeding risk. 137 Factor Xa DOACs also depend on the Pglycoprotein pathway for metabolism, and interactions with inducers and inhibitors have been described. Moreover, factor Xa DOACs are metabolized by cytochrome P450 and drug effectiveness may be affected by coadministration with CYP3A4 inhibitors (e.g., fluconazole, ketoconazole, itraconazole, and vorconazole) or CYP3A4 inducers (e.g., rifampin and phenytoin).…”

Physiologically‐based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate

“…A few PBPK models for DABE has been published so far. 31,35 Among these, the model developed by Moj et al is comprehensive and can predict DABE, DAB, and DAB-G. However, that model used the salt solubility of DABE (1.8 mg/ml) to develop the absorption model.…”

“…A few PBPK models for DABE has been published so far 31,35 . Among these, the model developed by Moj et al is comprehensive and can predict DABE, DAB, and DAB‐G.…”