Key result
Dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function produced trough and peak exposures (gMean 155 and 202 ng/mL) consistent with pharmacokinetic predictions.
Why the study?
Does dabigatran 75 mg twice daily provide appropriate pharmacokinetic exposure in patients with nonvalvular atrial fibrillation and severely impaired renal function?
Does dabigatran 75 mg twice daily provide appropriate pharmacokinetic exposure in patients with nonvalvular atrial fibrillation and severely impaired renal function?
Dabigatran 75 mg twice daily in patients with NVAF and severe renal impairment produces exposure levels consistent with prior pharmacokinetic modeling, supporting its FDA-approved use in this population.
Observed exposures matched PK model predictions for 75 mg BID; leaves open effects on clinical outcomes in severe renal impairment.
Introduction: Dabigatran etexilate is an oral direct thrombin inhibitor. Dabigatran excretion is 80% renal, so exposure increases with severity of renal failure. The US Food and Drug Administration-approved dabigatran etexilate 75 mg twice daily (BID) for patients with nonvalvular atrial fibrillation (NVAF) having severely impaired renal function (creatinine clearance: 15-30 mL/min), based on post hoc pharmacokinetic modeling. We assessed dabigatran exposure at trough and peak levels in patients with NVAF and severely impaired renal function and compared with model predictions. Methods: Patients received dabigatran etexilate (75 mg BID) for ≥7 days before blood sampling; C pre,ss (steady-state predose concentration; trough) was taken 10 to 16 hours postdose (prior to next dose), and C 2,ss (steady-state concentration; peak) was taken 2 hours (± 30 minutes) postdose. Pharmacodynamic parameters at baseline (E base ), trough concentrations (E pre,ss ), and peak concentrations (E 2,ss ) were assessed by established coagulation assays. Results: Of the 150 patients screened, 60 were treated, of which 40% were male and 78.3% were white; median age was 84 years. C pre,ss values (n = 51) were close to pharmacokinetic modeling predictions with a geometric mean (gMean) of 155 ng/mL, geometric coefficient of variation (gCV) of 76.9%, and range of 15.6 to 498 ng/mL. The C 2,ss values (n = 59) had a gMean of 202 ng/mL, gCV of 70.6%, and range of 42.0 to 680 ng/mL. Pharmacodynamic effects on coagulation paralleled dabigatran concentrations. Eleven (18.3%) patients had ≥1 adverse event (AE); pharmacokinetic results for these patients versus those without AEs (n = 49) were C pre, ss : gMean = 206 versus 145 ng/mL, gCV = 64.0% versus 78.3%; C 2,ss : gMean = 243 versus 193 ng/mL, gCV = 68.9% versus 70.8%. All bleeding events (8 events in 5 patients) were considered minor by the investigators. Conclusion: Dabigatran exposure levels largely confirmed earlier pharmacokinetic predictions, supporting the use of dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function. Pharmacodynamic results were also in agreement with earlier studies. Trial Registration: ClinicalTrials.gov NCT01896297.
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Martin et al. (2018) studied Nonvalvular atrial fibrillation and severely impaired renal function (n=60). Dabigatran etexilate vs. Pharmacokinetic modeling predictions was evaluated on Dabigatran exposure at trough (C pre,ss) and peak (C 2,ss) levels. Dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function produced trough and peak exposures (gMean 155 and 202 ng/mL) consistent with pharmacokinetic predictions.
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