title: Drug-induced QTc interval prolongation: a proposal towards an efficient and safe anticancer drug development.
abstract: The goal of drug development is to define potential risks and benefits of new therapies. Assessment of new drugs for their potential to alter cardiac repolarisation, prolong QTc interval and induce potentially fatal proarrhythmias such as 'torsade de pointes' is now one of the major goals during phase I-II studies. The results from these early phase clinical studies can profoundly influence 'go, no-go' decisions as well as decisions on the selection of optimal dose regimen for subsequent development, its delivery and conduct of pivotal clinical studies, including eligibility of patients. Increasingly, anticancer drugs are now also attracting attention with regard to their proarrhythmic safety. Unfortunately, regulatory guidelines focus essentially on non-cytotoxic drugs and there is no clear guidance available for evaluation of the potential of cytotoxic drugs to alter cardiac repolarisation during their development. We propose a strategy to assess the QT-liability of a cytotoxic agent in early phase I-II studies without compromising the objectives of these studies or patient access to potentially beneficial novel agents. A pragmatic and thoughtful strategy for the assessment of this proarrhythmic risk and its management, involving close collaboration between drug developers, regulatory agencies, oncologists and cardiologists, is essential for the development of these oncology agents.
authors.affiliation: Division of Medical Oncology, Clinical Pharmacology and New Drugs Development Unit, European Institute of Oncology, Via Ripamonti 435, 20141 Milano, Italy. giuseppe.curigliano@ieo.it
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Curigliano
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Fingert
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.forename: Cristiana
authors.initials: C
authors.lastname: Sessa
authors.forename: Elwyn
authors.initials: E
authors.lastname: Loh
authors.forename: Carlo
authors.initials: C
authors.lastname: Cipolla
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Pas
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
authors.forename: Rashmi
authors.initials: R
authors.lastname: Shah
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D013678:Technology, Pharmaceutical
chemical_list: D000970:Antineoplastic Agents