Received for publication July 11, 2007.
Revised November 3, 2007.
Accepted for publication November 5, 2007.

Alfuzosin Delays Cardiac Repolarization by a Novel Mechanism

Abstract

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) which was weakly positive at high doses. 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 reexamined whether nonclinical signals of QT risk for alfuzosin were truly absent. Alfuzosin significantly prolonged APD₆₀ 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 QTcF 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 increased whole cell peak sodium (hNa_v1.5) current significantly (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 two- and three-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 Na current. Nonclinical studies clearly show that alfuzosin increases plateau potential and prolongs APD and QT consistent with QT prolongation in man. The results challenge FDA grounds for the absolute primacy of TCQS based on the claim of a false negative nonclinical study on alfuzosin.

Key words: acquired long QT syndrome, cardiac electrophysiology, cardiac ion channels, cardiac physiology, pharmacology, prolonged QT