A Randomized Clinical Trial

Background and objectives There is a paucity of data available to describe drug dialyzability. Of the available information, most was obtained before implementation of modern hemodialysis membranes. Our study characterized dialyzability of the most commonly prescribed b-blockers in patients undergoing high-flux hemodialysis. Design, setting, participants, & measurements Patients on hemodialysis (n=8) were recruited to an open label, pharmacokinetic, four-way crossover trial. Single doses of atenolol, metoprolol, bisoprolol, and carvedilol were administered on separate days in random order to each patient. Plasma and dialysate drug concentrations were measured, and dialyzability was determined by the recovery clearance and arterial venous difference methods. ResultsUsing the recoveryclearancemethod, thedialytic clearancevalues for atenolol,metoprolol, bisoprolol, and carvedilol were 72, 87, 44, and 0.2 ml/min, respectively (P,0.001). Applying the arterial venous difference method, the dialytic clearance values of atenolol, metoprolol, bisoprolol, and carvedilol were 167, 114, 96, and 24 ml/min, respectively (P,0.001). Conclusions Atenolol and metoprolol are extensively cleared by hemodialysis compared with the negligible dialytic clearance of carvedilol. Contrary to estimates of dialyzability on the basis of previous literature, our data indicate that bisoprolol is also dialyzable. This finding highlights the importance of conducting dialyzability studies to definitively characterize drug dialytic clearance. Clin J Am Soc Nephrol 13: 604–611, 2018. doi: https://doi.org/10.2215/CJN.07470717 Introduction The importance of cardiovascular disease among patients with CKD cannot be overstated. It accounts for nearly 45% of deaths among patients on hemodialysis, an incidence 10–20 times greater than in the general population (1–3). Over the past four decades, b-adrenergic receptor antagonists (b-blockers) have emerged as a fundamental component of treating cardiovascular disease. b-Blockers decrease BP, heart rate, myocardial oxygen demand, arrhythmia, and oxidative stress, and they improve left ventricular function (4). More importantly, their ability to reduce mortality has been shown in numerous randomized clinical trials (5–8). Although b-blockers are widely prescribed in patients on hemodialysis, this is on the basis of their proven efficacy in patients with normal kidney function. Extrapolating findings from the general population to patients with CKD has a number of caveats. The pharmacokinetics of many drugs are altered in CKD, including both kidneyand nonkidney-mediated elimination (9–11). Expectations that b-blockers will deliver similar therapeutic efficacy in patients on hemodialysis compared with the general population are based on very little evidence. For drugs to be approved for use in patients, detailed pharmacokinetic analysis must be undertaken to characterize parameters, such as bioavailability, metabolic elimination, and kidney-mediated drug clearance. The majority of drugs are not tested in patients on dialysis during the drug development process, which results in a lack of appropriate dosage recommendations (12– 15). Drug disposition is an especially important consideration in patients on hemodialysis because there is minimal to no residual kidney function for drug excretion. Despite requirements to characterize kidneymediated elimination during drug development, there are very minimal data on drug clearance in patients on hemodialysis. Specifically, drug dialyzability—the efficiency of drug removal by dialysis—is likely to vary among b-blockers, which should be considered when they are prescribed to patients. The use of drugs that are highly dialyzed can result in subtherapeutic plasma concentrations during and after hemodialysis and increase the risk for adverse clinical outcomes (16). Currently, definitive data on drug dialyzability are only available for 10% of medications. The dialyzability of b-blockers is presumed largely on the basis of physicochemical characteristics and not experimental evidence (17). Of the available information, most data were obtained before implementation of modern high-flux dialysis membranes, rendering many of the older studies irrelevant (18). Therefore, this study was conducted to define the modern dialyzability of the most commonly used b-blockers. Departments of