85 (0.81–0.90)  rs4122238 [13] 0.86 (0.81–0.91)  rs8192935 [13] 0.89 (0.85–0.93) Renal impairment [16]  Mild 1.50 (0.78–2.90)  Moderate 3.15 (1.63–6.08)

 Severe 6.31 (3.54–11.25) AUC 0–∞ area under the concentration-time curve from zero to infinity, CES1 carboxylesterase-1, NA not available, P-gp P-glycoprotein aThis represents the mean ratio of the AUC0–∞ of individuals with the covariate to healthy controls without the covariate, or, for genetic polymorphisms, the mean ratio 4SC-202 molecular weight (95 % CI) of either peak (P-gp) or trough (CES1) concentrations of single allele carriers to wildtype bSteady-state dosing of clopidogrel has not been shown to significantly alter dabigatran AUC0–∞ [7] cMay be associated with decreased dabigatran AUC0–∞ [10] As dabigatran is mainly cleared by the kidneys (fraction excreted unchanged in urine of 0.8), renal function is a major determinant of dabigatran concentrations [15, 16]. Glucuronidation is responsible for the remaining 20 % of dabigatran

clearance [15, 17]. The dabigatran glucuronides are equipotent to dabigatran Fosbretabulin solubility dmso against thrombin, and appear to be primarily renally cleared [15, 17]. Hence, it has been recommended that maintenance dose rates of dabigatran etexilate should be adjusted to take renal function into account [5, 18]. The standard representation of renal function is the glomerular filtration rate (GFR) [19, 20]. The gold standard methods for determining GFR are based on the clearance of renally eliminated exogenous compounds Salubrinal solubility dmso [21]. However, as these are inconvenient for routine clinical use, several equations for estimating GFR based on the measurement of endogenous compounds are currently recommended [19, 20]. The Cockcroft–Gault (CG) equation [22], which uses the endogenous renal biomarker, creatinine, has been used for many years to gauge renal function in relation to drug dosing [23].

More recently, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 equation [24] was developed to using creatinine assays standardised against the isotope dilution mass spectrometry (IDMS) method, and has become one of the most commonly used GFR equations [25, 26]. Cystatin C is an alternative renal function biomarker that has received considerable attention [27]. Whereas creatinine assay standardisation was introduced in 2006, the first certified reference material (ERM-DA471/IFCC) for standardising cystatin C assays has only been available since 2010 [28]. Hence, while a multitude of cystatin C-based GFR equations have been developed over the years [29], only a few have employed assays that are traceable to ERM-DA471/IFCC [30, 31]. These include the CKD-EPI equations that feature cystatin C [30]. All GFR equations are expected to explain some of the variance in dabigatran concentrations.