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

Figures

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  Figure 1. Simulated and observed plasma concentration–time profiles of dabigatran etexilate (DABE; red) and dabigatran (DAB; blue) after a single oral dose (SD) or multiple doses (MD) of 150 mg DABE. (a) DABE SD alone in healthy volunteer (HV), (b) DABE MD alone in HV, (c) DABE SD 1 hour after verapamil (MD) in HV, (d) DABE SD 2 hours before verapamil (MD) in HV, and (e) DABE SD alone in the population with healthy renal function (creatinine clearance (CrCl) >80 mL/min) and in the populations with (f) mild (CrCl 50–80 mL/min), (g) moderate (CrCl 30–50 mL/min), and (h) severe (CrCl 15–30 mL/min) renal impairment. Simulation results are presented as the means of all 10 trials (heavy lines), 10 individual trials (thin lines), and 5th and 95th percentiles (dashed lines). Observed data extracted from the literature4, 6, 17, 18 are presented as the means (open circles).

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  Figure 2. Simulated and observed trough dabigatran concentrations after multiple dose (75, 110, or 150 mg b.i.d.) of dabigatran etexilate (DABE) without, concurrently with, or 2 hours before verapamil in the population with healthy renal function (creatinine clearance (CrCl) >80 mL/min) and the populations with mild (CrCl 50–80 mL/min), moderate (CrCl 30–50 mL/min), and severe (CrCl 15–30 mL/min) renal impairment. Virtual studies were simulated using 20 trials of 10 virtual individuals. Data are presented as the medians and 10th/90th percentiles of all 20 trials. Observed concentrations were calculated using dose‐normalized concentrations extracted from the literature (Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) Trial).10 Lower and upper dotted lines indicate 28 ng/mL with 50% increase in the risk of ischemic stroke or systemic embolism and 210 ng/mL with a doubled risk of major bleeding, respectively. b.i.d., twice a day.