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Open Access 01-06-2014 | Original Research Article

Correlation Between Trough Plasma Dabigatran Concentrations and Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C

Authors: Paul K. L. Chin, Daniel F. B. Wright, Mei Zhang, Mary C. Wallace, Rebecca L. Roberts, David M. Patterson, Berit P. Jensen, Murray L. Barclay, Evan J. Begg

Published in: Drugs in R&D | Issue 2/2014

Abstract

Aims

Dabigatran is largely cleared by renal excretion. Renal function is thus a major determinant of trough dabigatran concentrations, which correlate with the risk of thromboembolic and haemorrhagic outcomes. Current dabigatran dosing guidelines use the Cockcroft–Gault (CG) equation to gauge renal function, instead of contemporary equations including the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations employing creatinine (CKD-EPI_Cr), cystatin C (CKD-EPI_Cys) and both renal biomarkers (CKD-EPI_CrCys).

Methods

A linear regression model including the dabigatran etexilate maintenance dose rate, relevant interacting drugs and genetic polymorphisms (including CES1), was used to analyse the relationship between the values from each renal function equation and trough steady-state plasma dabigatran concentrations.

Results

The median dose-corrected trough steady-state plasma dabigatran concentration in 52 patients (38–94 years) taking dabigatran etexilate was 60 µg/L (range 9–279). The dose-corrected trough concentration in a patient on phenytoin and phenobarbitone was >3 standard deviations below the cohort mean. The CG, CKD-EPI_Cr, CKD-EPI_Cys and CKD-EPI_CrCys equations explained (R ², 95 % CI) 32 % (9–55), 37 % (12–60), 41 % (16–64) and 47 % (20–69) of the variability in dabigatran concentrations between patients, respectively. One-way analysis of variance (ANOVA) comparing the R ² values for each equation was not statistically significant (p = 0.74).

Discussion

Estimates of renal function using the four equations accounted for 32–47 % of the variability in dabigatran concentrations between patients. We are the first to provide evidence that co-administration of phenytoin/phenobarbitone with dabigatran etexilate is associated with significantly reduced dabigatran exposure.

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Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719–47. doi:10.1093/eurheartj/ehs253.PubMedCrossRef

Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, et al. Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Can J Cardiol. 2012;28(2):125–36. doi:10.1016/j.cjca.2012.01.021.PubMedCrossRef

Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e44S–88S. doi:10.1378/chest.11-2292.PubMedCentralPubMed

Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The Effect of Dabigatran Plasma Concentrations and Patient Characteristics on the Frequency of Ischemic Stroke and Major Bleeding in Atrial Fibrillation Patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol. 2014;63(4):321–8. doi:10.1016/j.jacc.2013.07.104.PubMedCrossRef

Huisman MV, Lip GY, Diener HC, Brueckmann M, van Ryn J, Clemens A. Dabigatran etexilate for stroke prevention in patients with atrial fibrillation: resolving uncertainties in routine practice. Thromb Haemost. 2012;107(5):838–47. doi:10.1160/TH11-10-0718.PubMedCrossRef

Brunet A, Hermabessiere S, Benain X. Pharmacokinetic and pharmacodynamic interaction of dronedarone and dabigatran in healthy subjects. Eur Heart J. 2011;32(Suppl. 1):313–631. doi:10.1093/eurheartj/ehr323.

Hartter S, Sennewald R, Schepers C, Baumann S, Fritsch H, Friedman J. Pharmacokinetic and pharmacodynamic effects of comedication of clopidogrel and dabigatran etexilate in healthy male volunteers. Eur J Clin Pharmacol. 2013;69(3):327–39. doi:10.1007/s00228-012-1304-8.PubMedCentralPubMedCrossRef

Hartter S, Sennewald R, Nehmiz G, Reilly P. Oral bioavailability of dabigatran etexilate (Pradaxa((R))) after co-medication with verapamil in healthy subjects. Br J Clin Pharmacol. 2013;75(4):1053–62. doi:10.1111/j.1365-2125.2012.04453.x.PubMedCentralPubMedCrossRef

Delavenne X, Ollier E, Basset T, Bertoletti L, Accassat S, Garcin A, et al. A semi-mechanistic absorption model to evaluate drug-drug interaction with dabigatran: application with clarithromycin. Br J Clin Pharmacol. 2013;76(1):107–13. doi:10.1111/bcp.12055.PubMedCentralPubMedCrossRef

10.

Hartter S, Koenen-Bergmann M, Sharma A, Nehmiz G, Lemke U, Timmer W, et al. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br J Clin Pharmacol. 2012;74(3):490–500. doi:10.1111/j.1365-2125.2012.04218.x.PubMedCentralPubMedCrossRef

11.

Stangier J, Eriksson BI, Dahl OE, Ahnfelt L, Nehmiz G, Stahle H, et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol. 2005;45(5):555–63. doi:10.1177/0091270005274550.PubMedCrossRef

12.

Stangier J, Stahle H, Rathgen K, Fuhr R. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 2008;47(1):47–59. doi:10.2165/00003088-200847010-00005.PubMedCrossRef

13.

Pare G, Eriksson N, Lehr T, Connolly S, Eikelboom J, Ezekowitz MD, et al. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation. 2013;127(13):1404–12. doi:10.1161/CIRCULATIONAHA.112.001233.PubMedCrossRef

14.

US Food and Drug Administration. Briefing information for the September 20, 2010, meeting of the cardiovascular and renal drugs advisory committee; 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM247244.pdf. Accessed 9 Sep 2013.

15.

Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36(2):386–99. doi:10.1124/dmd.107.019083.PubMedCrossRef

16.

Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet. 2010;49(4):259–68. doi:10.2165/11318170-000000000-00000.PubMedCrossRef

17.

Ebner T, Wagner K, Wienen W. Dabigatran acylglucuronide, the major human metabolite of dabigatran: in vitro formation, stability, and pharmacological activity. Drug Metab Dispos. 2010;38(9):1567–75. doi:10.1124/dmd.110.033696.PubMedCrossRef

18.

Chin PK, Vella-Brincat JW, Barclay ML, Begg EJ. Perspective on dabigatran etexilate dosing: why not follow standard pharmacological principles? Br J Clin Pharmacol. 2012;74(5):734–40. doi:10.1111/j.1365-2125.2012.04266.x.PubMedCentralPubMedCrossRef

19.

KDIGO. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 2012;2:1–138.CrossRef

20.

KDIGO. KDIGO clinical practice guideline for chronic kidney disease. Kidney Int Suppl. 2013;3:1–150.CrossRef

21.

Florkowski CM, Chew-Harris JS. Methods of estimating GFR—different equations including CKD-EPI. Clin Biochem Rev. 2011;32(2):75–9.PubMedCentralPubMed

22.

Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.PubMedCrossRef

23.

Matzke GR, Aronoff GR, Atkinson AJ Jr, Bennett WM, Decker BS, Eckardt KU, et al. Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2011;80(11):1122–37. doi:10.1038/ki.2011.322.PubMedCrossRef

24.

Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12. (pii: 150/9/604).PubMedCentralPubMedCrossRef

25.

Earley A, Miskulin D, Lamb EJ, Levey AS, Uhlig K. Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review. Ann Intern Med. 2012;156(11):785–95. doi:10.1059/0003-4819-156-6-201203200-00391.PubMedCrossRef

26.

Howey OK, Chin PK. Usage of renal function equations to guide prescribing in general medicine. N Z Med J. 2013;126(1383):97–9.PubMed

27.

Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H. Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate. Acta Med Scand. 1985;218(5):499–503.PubMedCrossRef

28.

Grubb A, Blirup-Jensen S, Lindstrom V, Schmidt C, Althaus H, Zegers I, et al. First certified reference material for cystatin C in human serum ERM-DA471/IFCC. Clin Chem Lab Med. 2010;48(11):1619–21. doi:10.1515/CCLM.2010.318.PubMedCrossRef

29.

Chew JS, Saleem M, Florkowski CM, George PM. Cystatin C—a paradigm of evidence based laboratory medicine. Clin Biochem Rev. 2008;29(2):47–62.PubMedCentralPubMed

30.

Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20–9. doi:10.1056/NEJMoa1114248.PubMedCrossRef

31.

Schaeffner ES, Ebert N, Delanaye P, Frei U, Gaedeke J, Jakob O, et al. Two novel equations to estimate kidney function in persons aged 70 years or older. Ann Intern Med. 2012;157(7):471–81. doi:10.7326/0003-4819-157-7-201210020-00003.PubMedCrossRef

32.

Chin PK, Vella-Brincat JW, Walker SL, Barclay ML, Begg EJ. Dosing of dabigatran etexilate in relation to renal function and drug interactions at a tertiary hospital. Intern Med J. 2013;43(7):778–83. doi:10.1111/imj.12170.PubMedCrossRef

33.

Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest. 2010;137(2):263–72. doi:10.1378/chest.09-1584.PubMedCrossRef

34.

Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–100. doi:10.1378/chest.10-0134.PubMedCrossRef

35.

Mathew TH. Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: a position statement. Med J Aust. 2005;183(3):138–41.PubMed

36.

Stevens LA, Levey AS. Use of the MDRD study equation to estimate kidney function for drug dosing. Clin Pharmacol Ther. 2009;86(5):465–7. doi:10.1038/clpt.2009.124.PubMedCrossRef

37.

Spruill WJ, Wade WE, Cobb HH 3rd. Continuing the use of the Cockcroft–Gault equation for drug dosing in patients with impaired renal function. Clin Pharmacol Ther. 2009;86(5):468–70. doi:10.1038/clpt.2009.187.PubMedCrossRef

38.

Chin PK, Florkowski CM, Begg EJ. The performances of the Cockcroft–Gault, modification of diet in renal disease study and chronic kidney disease epidemiology collaboration equations in predicting gentamicin clearance. Ann Clin Biochem. 2013;50(Pt 6):546–57. doi:10.1177/0004563213492320.PubMedCrossRef

39.

Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317(17):1098. doi:10.1056/NEJM198710223171717.PubMed

40.

Selvin E, Juraschek SP, Eckfeldt J, Levey AS, Inker LA, Coresh J. Within-person variability in kidney measures. Am J Kidney Dis. 2013;61(5):716–22. doi:10.1053/j.ajkd.2012.11.048.PubMedCentralPubMedCrossRef

41.

Chew-Harris JS, Florkowski CM, George PM, Elmslie JL, Endre ZH. The relative effects of fat versus muscle mass on cystatin C and estimates of renal function in healthy young men. Ann Clin Biochem. 2013;50(Pt 1):39–46. doi:10.1258/acb.2012.011241.PubMedCrossRef

42.

Shlipak MG, Mattes MD, Peralta CA. Update on cystatin C: incorporation into clinical practice. Am J Kidney Dis. 2013;62(3):595–603. doi:10.1053/j.ajkd.2013.03.027.PubMedCentralPubMedCrossRef

43.

Delavenne X, Moracchini J, Laporte S, Mismetti P, Basset T. UPLC MS/MS assay for routine quantification of dabigatran—a direct thrombin inhibitor—in human plasma. J Pharm Biomed Anal. 2012;58:152–6. doi:10.1016/j.jpba.2011.09.018.PubMedCrossRef

44.

Ciulla TA, Sklar RM, Hauser SL. A simple method for DNA purification from peripheral blood. Anal Biochem. 1988;174(2):485–8.PubMedCrossRef

45.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–75. doi:10.1086/519795.PubMedCentralPubMedCrossRef

46.

Filler G, Bokenkamp A, Hofmann W, Le Bricon T, Martinez-Bru C, Grubb A. Cystatin C as a marker of GFR—history, indications, and future research. Clin Biochem. 2005;38(1):1–8. doi:10.1016/j.clinbiochem.2004.09.025.PubMedCrossRef

47.

Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis. 2012;23(2):138–43. doi:10.1097/MBC.0b013e32834f1b0c.PubMedCrossRef

48.

Boehringer Ingelheim Pharma GmbH & Co. KG. Pradaxa. Summary of Product Characteristics. European Medicines Agency. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf. Accessed 5 Jan 2014.

49.

Begg EJ, Chin PK. A unified pharmacokinetic approach to individualized drug dosing. Br J Clin Pharmacol. 2012;73(3):335–9. doi:10.1111/j.1365-2125.2011.04089.x.PubMedCentralPubMedCrossRef

50.

Hellden A, Odar-Cederlof I, Nilsson G, Sjoviker S, Soderstrom A, Euler M et al. Renal function estimations and dose recommendations for dabigatran, gabapentin and valaciclovir: a data simulation study focused on the elderly. BMJ Open. 2013;3(4). doi:10.1136/bmjopen-2013-002686.

51.

MacCallum PK, Mathur R, Hull SA, Saja K, Green L, Morris JK, et al. Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation: a cross-sectional study. BMJ Open. 2013;3(9):e003343. doi:10.1136/bmjopen-2013-003343.PubMedCentralPubMedCrossRef

52.

Duffull SB, Wright DF, Al-Sallami HS, Zufferey PJ, Faed JM. Dabigatran: rational dose individualisation and monitoring guidance is needed. N Z Med J. 2012;125(1357):148–54.PubMed

53.

Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129(9):961–70. doi:10.1161/CIRCULATIONAHA.113.003628.PubMedCrossRef

54.

Chin PK, Wright DF, Patterson DM, Doogue MP, Begg EJ. A proposal for dose-adjustment of dabigatran etexilate in atrial fibrillation guided by thrombin time. Br J Clin Pharmacol. 2014. doi:10.1111/bcp.12364.

55.

Schuetz EG, Beck WT, Schuetz JD. Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996;49(2):311–8.PubMed

56.

Stangier J, Stahle H, Rathgen K, Roth W, Shakeri-Nejad K. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment. J Clin Pharmacol. 2008;48(12):1411–9. doi:10.1177/0091270008324179.PubMedCrossRef

57.

Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol. 2007;64(3):292–303. doi:10.1111/j.1365-2125.2007.02899.x.PubMedCentralPubMedCrossRef

58.

US Food and Drug Administration. Guidance for industry: bioanalytical method validation; 2001. http://www.fda.gov/downloads/Drugs/Guidances/ucm070107.pdf. Accessed 6 April 2013.

59.

Boehringer Ingelheim (N.Z.) Limited. Pradaxa: New Zealand Datasheet. Medsafe; 2013. http://www.medsafe.govt.nz/profs/Datasheet/p/Pradaxacap.pdf. Accessed 28 Oct 2013.

Title: Correlation Between Trough Plasma Dabigatran Concentrations and Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C
Authors: Paul K. L. Chin
Daniel F. B. Wright
Mei Zhang
Mary C. Wallace
Rebecca L. Roberts
David M. Patterson
Berit P. Jensen
Murray L. Barclay
Evan J. Begg
Publication date: 01-06-2014
Publisher: Springer International Publishing
Published in: Drugs in R&D / Issue 2/2014
Print ISSN: 1174-5886
Electronic ISSN: 1179-6901
DOI: https://doi.org/10.1007/s40268-014-0045-9

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Correlation Between Trough Plasma Dabigatran Concentrations and Estimates of Glomerular Filtration Rate Based on Creatinine and Cystatin C

Abstract

Aims

Methods

Results

Discussion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aims

Methods

Results

Discussion

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