Author + information
- Judith Kooiman, MD, PhD∗ (, )
- Tom van der Hulle, MD,
- Hugo Maas, PhD,
- Sabrina Wiebe, MSc,
- Stephan Formella, MD,
- Andreas Clemens, MD,
- Marjolijn van Buren, MD, PhD,
- Martien Janssen, MD, PhD,
- Ton J. Rabelink, MD, PhD and
- Menno V. Huisman, MD, PhD
- ↵∗Department of Thrombosis and Hemostasis, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, the Netherlands
Dabigatran etexilate (dabigatran) is a direct oral thrombin inhibitor approved for the prevention of ischemic stroke in patients with nonvalvular atrial fibrillation. Dabigatran has ∼80% renal excretion, so patients with creatinine clearance (CrCl) <30 ml/min were excluded from phase 3 studies. On the basis of post hoc pharmacokinetic (PK) modeling (1,2), the U.S. Food and Drug Administration approved a lower dose of 75 mg twice daily (b.i.d.) for patients with severe chronic kidney disease (CKD) (CrCl 15 to 30 ml/min). This study prospectively investigates the PK and pharmacodynamics of dabigatran 75 mg b.i.d. in patients with severe CKD and compares the observed PK data with predictions from 2 PK models (1,3).
We performed an open-label, single-center study in which patients received dabigatran 75 mg b.i.d. for 7.5 days (15 administrations) followed by 4-day wash-out. Inclusion criteria were stable CrCl (Cockcroft-Gault formula) between 15 to 30 ml/min over the last 3 months (change in creatinine <20%), age <18 years, and treatment with vitamin K antagonists (VKA) or aspirin (any indication). Important exclusion criteria were: >1 platelet aggregation inhibitor, uncontrolled hypertension, previous hemorrhagic stroke, or gastrointestinal bleeding.
Patients stopped aspirin or VKA treatment 5 to 7 days prior to the first study day. Patients on VKA treatment received the first dabigatran dose when prothrombin time-international normalized ratio <2.0. Blood samples were collected every 24 h, with full profiles obtained over the dosing interval on the first and last day of dabigatran intake.
Primary endpoints were dabigatran plasma PK parameters: Cmax,ss (maximum measured concentration in plasma at steady-state) and AUCƮ,ss (area under the concentration-time curve at steady-state, over an interval Ʈ of 12 h). A graphical comparison was made between the means of observed and predicted total dabigatran concentrations (on the basis of 2 PK models) (1,3). The effect of dabigatran on blood coagulation was assessed using activated partial thromboplastin time, ecarin clotting time, and diluted thrombin time.
In 2013, 16 patients entered the study: 11 were taking aspirin and 5 taking VKA pre-treatment. Mean age was 73 ± 8 years, and 81.3% were male. Mean CrCl was 22.8 ml/min (range 15.0 to 33.0 ml/min). One patient’s data was excluded due to CrCl miscalculation (33 ml/min). Patients took their trial medication as planned, although 1 patient forgot her evening dose on day 3. No cardiovascular or major bleeding events occurred.
Total dabigatran PK values expressed as median (10th to 90th percentiles) were as follows: Cmax (maximum concentration of the analyte in plasma measured after the first dose administration) 59.2 ng/ml (30.8 to 91.9 ng/ml), Cpre,ss,15 (pre-dose plasma concentration of the analyte at steady state immediately before administration of the last [15th] dose) 176 ng/ml (99.3 to 359.0 ng/ml), Cmax,ss 215 ng/ml (116 to 365 ng/ml), AUCƮ,ss 2,270 ng·h/ml (1,160 to 3,800 ng·h/ml), and t1/2,ss (terminal half-life at steady state for the last dose administration) 27.8 h (25.5 to 31.7 h). We compared the observed mean concentration-time profile of total dabigatran with predicted values of 2 PK models (Figure 1).
Model I predicts the observed pre-dose means adequately, but tends to overpredict the peak. Model II tends to underpredict the pre-dose means, but adequately describes the peak. Deviations lie within the range of uncertainty. Furthermore, all observed means are within the concentration range intended at the time of selection of the 75-mg b.i.d. dose.
Mean baseline aPTT was 28.7 ± 3.2 s; 56.2 ± 7.3 s was the maximum at steady-state. For dTT, these values were 30.1 ± 2.5 s and 65.5 ± 16.9 s, respectively. Maximum ECT values at baseline and steady-state were 37.4 ± 2.9 s and 123.0 ± 35.7 s, respectively.
Our study has 2 main findings. First, the 75-mg b.i.d. dabigatran regimen results in mean steady-state drug exposure in patients with stable severe CKD comparable to predicted exposure, confirming the outcomes of the PK models used to establish the U.S. Food and Drug Administration–approved dabigatran dose for this population (1,3). Second, our results indicate that the 75-mg b.i.d. dabigatran regimen does not result in drug accumulation beyond 5 days of treatment.
Our results should be interpreted with certain considerations. Included patients had varying indications for either aspirin or VKA use. Moreover, our study was not designed to study the efficacy and safety of dabigatran in patients with severe CKD.
In conclusion, our study findings indicate that the dabigatran 75-mg b.i.d. regimen achieves predicted drug exposure in patients with severe CKD without accumulation beyond 5 days of treatment. Future clinical studies are needed to study the clinical efficacy and safety of dabigatran relative to warfarin in this specific patient population.
Please note: The authors thank Prof. Dr. F.W.G. Leebeek (Erasmus Medical Center, Rotterdam, the Netherlands) for his role as independent physician in this study. This study was initiated by the Leiden University Medical Center and was supported with a grant from Boehringer Ingelheim. Drs. Kooiman, van der Hulle, Rabelink, and Huisman are full-time employees of the Leiden University Medical Center. Drs. Maas, Formella and Wiebe are full-time employees of Boehringer Ingelheim Pharma. Dr. Clemens was a full-time employee of Boehringer Ingelheim and is a current full-time employee at Novartis Pharma. Dr. van Buren is an employee of the Leiden University Medical Center and the Haga Teaching Hospital. Dr. Janssen is an employee of the Alrijne Hospital. Dr. Huisman has received grant support and lecture fees from Actelion, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and GlaxoSmithKline. (Study to Evaluate the Pharmacokinetics and Pharmacodynamics of Dabigatran Etexilate in Patients With Stable Severe Renal Disease; NCT01711853.)
- 2016 American College of Cardiology Foundation