Withdrawal of prenylamine: perspectives on pharmacological, clinical and regulatory outcomes following the first QT-related casualty

Abstract

Prenylamine, an antianginal agent marketed since early 1960, became the first casualty of QT interval related proarrhythmias in 1988 when it was withdrawn from the market. The period of its synthesis and marketing is of particular interest since it antedated, first, any serious clinical safety concern regarding drug-induced prolongation of the QT interval which was, in fact, believed to be an efficient antiarrhythmic mechanism; second, the first description of torsade de pointes as a unique proarrhythmia, typically associated with prolonged QT interval; and third, the discovery and recognition of calcium antagonism as an important cardiovascular therapeutic strategy. This review, 30 years almost to the day following its withdrawal, provides interesting perspectives on clinical, pharmacological and regulatory outcomes that followed. Prenylamine underscored torsadogenic potential of other early antianginal drugs on the market at that time and identified QT-related proarrhythmias as a much wider major public health issue of clinical and regulatory concern. This resulted in various guidelines for early identification of this potentially fatal risk. Application of these guidelines would have readily identified its proarrhythmic potential. Prenylamine also emphasized differences in drug responses between men and women which subsequently galvanized extensive research into sex-related differences in pharmacology. More importantly, however, investigations into the mechanisms of its action paved the way to developing modern safe and effective calcium antagonists that are so widely used today in cardiovascular pharmacotherapy.

Effect of gender, age and vaccine on reactogenicity and incapacity to work after COVID-19 vaccination: a survey among health care workers

“…In consequence, 80% of drug withdrawals from the U.S. market were ascribable to new health risks found in women [ 17 ]. This gender discrepancy in side effects cannot only be explained by differences in pharmacokinetics [ 18 ], but also in pharmacodynamics, as shown by the higher risk for QT-prolongation [ 19 ].…”

Human Pluripotent Stem Cell-Derived Cardiomyocytes for Assessment of Anticancer Drug-Induced Cardiotoxicity

“…Interestingly, a calcium antagonistic compound called prenylamine, was able to reduce cardiotoxic effects when co-administered with Doxorubicin, before it was withdrawn from the market 1 year later (80). Reason for withdrawal was the pro-arrhythmic properties of prenylamine, inducing long QT syndrome (81). Other calcium agonists are currently primarily used at lower doses to reduce Doxorubicin resistance of cancer cells, by inhibiting their capacity to pump out drugs via the Pglycoprotein ATP-dependent efflux pumps (82).…”

Data-driven drug-induced QT prolongation surveillance using adverse reaction signals derived from 12-lead and continuous electrocardiogram data

“…Drug-induced QT prolongation is the most common cause of acquired QT prolongation [ 5 , 6 ]. Furthermore, A drug’s propensity to cause QT interval prolongation may cause its withdrawal from the market [ 7 ]. Accordingly, the early detection of drug-induced QT prolongation is crucial from the medical and socioeconomic perspectives.…”