The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency

Introduction: Carvedilol, a chiral compound possessing nonselective beta- a nd alpha(1)-blocking activity, is used for the treatment of hypertension an d congestive heart failure (CHF). The enantiomers of carvedilol exhibit sim ilar at-blocking activity; only S-carvedilol possesses beta-blocking activi ty. Carvedilol is primarily hepatically metabolized, with less than 2% of t he dose excreted renally as unchanged drug. Methods: The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients wi th hypertension and advanced renal insufficiency not yet on dialysis [GFR l ess than or equal to 30 ml . min(-1) (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Day s 2-9) dosing. Results: Mean with (SD) AUC((0-24h)) (ng . h . ml(-1)) for carvedilol was 2 20 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in con trols on Days 1 and 9, respectively, primarily due to higher R-carvedilol c oncentrations. Mean with (SD) C-max (ng . ml(-1)) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in co ntrols on Days 1 and 9, respectively. The difference in group mean values w as characterized by considerable overlap in individual AUC((0-24h)) and C-m ax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Les s than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree. Conclusion: Compared with controls, average AUC((0-24 h)) values for carved ilol were approximately 40% and 50% higher on study Days 1 and 9 in patient s with renal insufficiency, primarily due to higher R-carvedilol concentrat ions with only a small change (<20%) in S-carvedilol concentrations, the is omer possessing beta-blocking activity. These changes in pharmacokinetics a re modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with modera te/severe renal insufficiency.