Controlled-Release Carvedilol: A Concluding Perspective

Abstract

d d t c h I e p p b s a s b a p d a f t The studies summarized in this supplement to The merican Journal of Cardiology demonstrate that a new ontrolled-release (CR) formulation of carvedilol has een developed that is bioequivalent to the currently arketed immediate-release (IR) formulation of the drug. uch development is noteworthy because carvedilol has een shown in numerous placebo-controlled trials to have mportant clinical benefits across a wide range of cardioascular disorders,1–5 and these effects may not be eadily replicated with other -blocker drugs.5–7 What does bioequivalence mean? From a technical viewoint, it means that key pharmacokinetic (PK) parameters, ncluding peak and trough concentrations and area under the oncentration curve, were nearly identical for the IR and CR ormulations, with confidence intervals that were within the enerally accepted limits of bioequivalence. From a practial viewpoint, it means that patients taking either formulaion could be switched to the other formulation without any eaningful change in exposure to the drug. The available tudies demonstrated bioequivalence across the spectrum of atients with approved indications for carvedilol, including hose with the following: hypertension; left ventricular dysunction (LVD) after an acute myocardial infarction (MI); nd mild, moderate, or severe heart failure. Why is the development of this formulation important? he development of a CR formulation that is bioequivalent o an IR formulation represents an uncommon achievement n medicinal chemistry. Most long-acting versions of shortcting drugs produce peak and trough concentrations that iffer meaningfully from the IR formulation. Such PK diferences raise the possibility that the efficacy and safety of he new CR formulation may not reproduce the efficacy and afety of the already marketed IR agent. This uncertainty is nderscored by the fact that the precise PK characteristics hat determine the efficacy and safety of a particular theraeutic agent are generally unknown. In some instances, the enefits of a drug may depend on the achievement of speific peak concentrations, whereas for some drugs, high eak levels may contribute little to efficacy but may inrease the risk of intolerance. In other circumstances, the rug benefit may rely heavily on the maintenance of minium trough levels; however, for many agents, low plasma