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Abstract
Introduction: Carvedilol, a chiral compound possessing nonselective β- and α^sub 1^-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar α^sub 1^-blocking activity; only S-carvedilol possesses β-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the 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 with hypertension and advanced renal insufficiency not yet on dialysis [GFR≤30ml·min^sup -1^ (CRI, chronic renal insufficiency), n=12] following single (12.5mg, Day 1) and multiple (25mg once daily, Days 2-9) dosing.
Results: Mean with (SD) AUC^sub (0-24h)^ (ng·h·ml^sup -1^) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) C^sub max^ (ng·ml^sup -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 controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC^sub (0-24h)^ and C^sub max^ values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less 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^sub (0-24h)^ values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing β-blocking activity. These changes in pharmacokinetics are 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 moderate/severe renal insufficiency.[PUBLICATION ABSTRACT]