title: An open-label study of the pharmacokinetics and pharmacodynamics of dabigatran etexilate 150mg once daily in Caucasian patients with moderate renal impairment undergoing primary unilateral elective total knee or hip replacement surgery.
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.
authors.affiliation: University of Gothenburg, Sahlgrenska University Hospital/Mölndal, Mölndal, Sweden. Electronic address: bengt.eriksson@gu.se.
authors.forename: Bengt I
authors.initials: BI
authors.lastname: Eriksson
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria. Electronic address: zsolt.mikuska@boehringer-ingelheim.com.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Mikuska
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. Electronic address: martin.feuring@boehringer-ingelheim.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Feuring
authors.affiliation: HYPHEN BioMed, Neuville-sur-Oise, France. Electronic address: jamiral@hyphen-biomed.com.
authors.forename: Jean
authors.initials: J
authors.lastname: Amiral
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA. Electronic address: sebastian.haertter@boehringer-ingelheim.com.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Haertter
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. Electronic address: joachim.stangier@boehringer-ingelheim.com.
authors.forename: Joachim
authors.initials: J
authors.lastname: Stangier
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany. Electronic address: gerhard.nehmiz.ext@boehringer-ingelheim.com.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Nehmiz
authors.affiliation: McMaster University and the Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada. Electronic address: weitzj@taari.ca.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Weitz
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000991:Antithrombins / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use*; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D002170:Canada / Q000453:epidemiology; D000069604:Dabigatran / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology / Q000627:therapeutic use*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D051437:Renal Insufficiency / Q000150:complications; D054556:Venous Thromboembolism / Q000453:epidemiology / Q000517:prevention & control*; D044465:White People
chemical_list: D000991:Antithrombins; D000069604:Dabigatran
keywords: Assay; Dabigatran etexilate; Orthopedic surgery; Pharmacokinetics; Renal impairment; Venous thromboembolism