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CARDIOVASCULAR

Alfuzosin Delays Cardiac Repolarization by a Novel Mechanism

ChanTest Corporation, Cleveland, Ohio (A.E.L., Y.A.K., Y.C., M.R., H.E., S.J.D., J.W.K., T.Y., A.M.B.); and Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio (A.M.B.)

The United States Food and Drug Administration (FDA) uses alfuzosin as an example of a drug having QT risk in humans that was not detected in nonclinical studies. FDA approval required a thorough clinical QT study (TCQS) that was weakly positive at high doses. The FDA has used the clinical/nonclinical discordance as a basis for mandatory TCQS, and this requirement has serious consequences for drug development. For this reason, we re-examined whether nonclinical signals of QT risk for alfuzosin were truly absent. Alfuzosin significantly prolonged action potential duration (APD)₆₀ in rabbit Purkinje fibers (p < 0.05) and QT in isolated rabbit hearts (p < 0.05) at the clinically relevant concentration of 300 nM. In man, the QT interval corrected with Fridericia's formula increased 7.7 ms, which exceeds the 5.0-ms threshold for a positive TCQS. Effects on hK_v11.1, hK_v4.3, and hK_v7.1/hKCNE1 potassium currents and calcium current were not involved. At 300 nM, 30x C_max, alfuzosin significantly increased whole-cell peak sodium (hNa_v1.5) current (p < 0.05), increased the probability of late hNa_v1.5 single-channel openings, and significantly shortened the slow time constant for recovery from inactivation. Alfuzosin also increased hNa_v1.5 burst duration and number of openings per burst between 2- and 3-fold. Alfuzosin is a rare example of a non-antiarrhythmic drug that delays cardiac repolarization not by blocking hK_v11.1 potassium current, but by increasing sodium current. Nonclinical studies clearly show that alfuzosin increases plateau potential and prolongs APD and QT, consistent with QT prolongation in man. The results challenge the FDA grounds for the absolute primacy of TCQS based on the claim of a false-negative, nonclinical study on alfuzosin.

Address correspondence to: Dr. Antonio E. Lacerda, ChanTest Corporation, 14656 Neo Parkway, Cleveland, OH 44128. E-mail: alacerda{at}chantest.com