Bengt I Eriksson1, Zsolt Mikuska2, Martin Feuring3, Jean Amiral4, Sebastian Haertter5, Joachim Stangier6, Gerhard Nehmiz7, Jeffrey I Weitz8. 1. University of Gothenburg, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden. Electronic address: bengt.eriksson@gu.se. 2. Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria. Electronic address: zsolt.mikuska@boehringer-ingelheim.com. 3. Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. Electronic address: martin.feuring@boehringer-ingelheim.com. 4. HYPHEN BioMed, Neuville-sur-Oise, France. Electronic address: jamiral@hyphen-biomed.com. 5. Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA. Electronic address: sebastian.haertter@boehringer-ingelheim.com. 6. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. Electronic address: joachim.stangier@boehringer-ingelheim.com. 7. Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. Electronic address: gerhard.nehmiz.ext@boehringer-ingelheim.com. 8. McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada. Electronic address: weitzj@taari.ca.
Abstract
BACKGROUND: In adults with moderate renal impairment (creatinine clearance [CrCl] 30-50mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of dabigatran etexilate is 150mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. METHODS: Single-arm, open-label phase 4 study (NCT01184989) in Caucasian patients receiving dabigatran etexilate 75mg 1-4h after surgery and 150mg qd on days 2-10 (TKR) or days 2-35 (THR). Plasma total dabigatran concentrations (day 6±1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). RESULTS: Of 112 patients (mean CrCl 42.5mL/min, age 79.1years, 69.6% female), 100 completed the study. Geometric mean trough and peak dabigatran concentrations were 47.5ng/mL (10th-90th percentile 19.7-120) and 166ng/mL (49.1-364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50-500ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ±15%. CONCLUSIONS: These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150mg qd dose of dabigatran etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of dabigatran levels would be helpful.
BACKGROUND: In adults with moderate renal impairment (creatinine clearance [CrCl] 30-50mL/min) undergoing total hip or knee replacement (THR/TKR), the recommended dose of dabigatran etexilate is 150mg once daily (qd). We investigated the steady state pharmacokinetics, pharmacodynamics and safety in these patients. METHODS: Single-arm, open-label phase 4 study (NCT01184989) in Caucasian patients receiving dabigatran etexilate 75mg 1-4h after surgery and 150mg qd on days 2-10 (TKR) or days 2-35 (THR). Plasma total dabigatran concentrations (day 6±1) were determined by high-performance liquid chromatography tandem mass spectrometry and indirectly using the commercially available diluted thrombin time (dTT) assay (Hemoclot® Thrombin Inhibitors). RESULTS: Of 112 patients (mean CrCl 42.5mL/min, age 79.1years, 69.6% female), 100 completed the study. Geometric mean trough and peak dabigatran concentrations were 47.5ng/mL (10th-90th percentile 19.7-120) and 166ng/mL (49.1-364), respectively. There were four major bleeding events and no venous thromboembolic events. Dabigatran concentrations determined from dTT (and falling within the assay range of 50-500ng/mL) underestimated actual values by 7.6% (90% confidence interval 5.3, 9.9), which is within the acceptance limits of ±15%. CONCLUSIONS: These findings in Caucasians with moderate renal impairment undergoing THR or TKR support the use of the 150mg qd dose of dabigatran etexilate. With adequate set-up, calibration and quality control the dTT assay might be appropriate for situations, such as serious bleeding or a need for urgent surgery, where determination of dabigatran levels would be helpful.