title: Renal function estimations and dose recommendations for dabigatran, gabapentin and valaciclovir: a data simulation study focused on the elderly.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  A retrospective data simulation study.
  
  
  METHODS
  Participants 65 years and older included in six different studies.
  
  
  METHODS
  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 m(2) 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.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Helldén
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Odar-Cederlöf
authors.forename: Göran
authors.initials: G
authors.lastname: Nilsson
authors.forename: Susanne
authors.initials: S
authors.lastname: Sjöviker
authors.forename: Anders
authors.initials: A
authors.lastname: Söderström
authors.forename: Mia von
authors.initials: Mv
authors.lastname: Euler
authors.forename: Gunnar
authors.initials: G
authors.lastname: Ohlén
authors.forename: Ulf
authors.initials: U
authors.lastname: Bergman