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Geriatric medicine
Research
Renal function estimations and dose recommendations for dabigatran, gabapentin and valaciclovir: a data simulation study focused on the elderly
  1. Anders Helldén1,
  2. Ingegerd Odar-Cederlöf1,
  3. Göran Nilsson2,
  4. Susanne Sjöviker3,
  5. Anders Söderström4,
  6. Mia von Euler1,5,
  7. Gunnar Öhlén6,
  8. Ulf Bergman1,7,8
  1. 1Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  2. 2Centre of Clinical Research, Uppsala University, Västerås, Sweden
  3. 3Department of Drug Management and Informatics, Centre for Health Care Improvement, Stockholm County Council, Stockholm, Sweden at the time of the study
  4. 4Farsta home care center at the time of the study, presently at Vendelsö home care center, Stockholm, Sweden
  5. 5Karolinska Institutet Stroke Research Network at Södersjukhuset, Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet
  6. 6Quality and Patient Safety, Karolinska University Hospital, Stockholm, Sweden, Karolinska University Hospital, Stockholm, Sweden
  7. 7Centre for Pharmacoepidemiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
  8. 8Division of Clinical Pharmacology, a partner in European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP), coordinated by the European Medicines Agency (EMA), Karolinska University Hospital, Stockholm, Sweden
  1. Correspondence to Dr Anders Helldén; anders.hellden{at}ki.se

Abstract

Objectives The thrombin inhibitor dabigatran is mainly excreted by the kidneys. We investigated whether the recommended method for estimation of renal function used in the clinical trials, the Cockcroft-Gault (CGold) equation and the estimated glomerular filtration rate (eGFR) modification of diet in renal disease equation 4 (MDRD4), differ in elderly participants, resulting in erroneously higher dose recommendations of dabigatran, which might explain the serious, even fatal, bleeding reported. The renally excreted drugs gabapentin and valaciclovir were also included for comparison.

Design A retrospective data simulation study.

Participants Participants 65 years and older included in six different studies.

Main outcome measure Estimated renal function by CG based on uncompensated (‘old Jaffe’ method) creatinine (CGold) or by MDRD4 based on standardised compensated P-creatinine traceable to isotope-dilution mass spectrometry, and the resulting doses.

Results 790 participants (432 females), mean age (±SD) 77.6±5.7 years. Mean estimated creatinine clearance (eCrCl) by the CGold equation was 44.2±14.8 ml/min, versus eGFR 59.6±20.7 ml/min/1.73 m2 with MDRD4 (p<0.001), absolute median difference 13.5, 95% CI 12.9 to 14.2. MDRD4 gave a significantly higher mean dose (valaciclovir +21%, dabigatran +25% and gabapentin +37%) of all drugs (p<0.001). With MDRD4 58% of the women would be recommended a full dose of dabigatran compared with 18% if CGold is used.

Conclusions MDRD4 would result in higher recommended doses of the three studied drugs to elderly participants compared with CG, particularly in women, and thus increased the risk of dose and concentration-dependent adverse reactions. It is important to know which method of estimation of renal function the Summary of Products Characteristics was based on, and use only that one when prescribing renally excreted drugs with narrow safety window. Doses based on recently developed methods for estimation of renal function may be associated with considerable risk of overtreatment in the elderly.

  • Clinical Pharmacology
  • Geriatric Medicine

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/3.0/ and http://creativecommons.org/licenses/by-nc/3.0/legalcode

https://doi.org/10.1136/bmjopen-2013-002686

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