Assessment of QT liabilities in drug development.
Since the publication, in 1997, of the CPMP (Committee for Proprietary Medicinal Products) Points to Consider document on "The assessment of potential for QT prolongation by non-cardiovascular medicinal products," both regulatory bodies and the pharmaceutical industry have paid increasing attention to the conduct of careful preclinical studies on the subject. Regulatory attention has focused on the drafting of Safety Pharmacology guidelines through the ICH (International Conference on Harmonization) process, which resulted in approval by the ICH and acceptance by the three main regions (USA, Europe, and Japan) of the ICH S7A guideline. The guideline does not deal only with cardiovascular studies and does not provide guidance on QT investigations. This part has been deferred to a second guideline (ICH S7B). Nevertheless, pharmaceutical companies have implemented screening strategies aimed at selecting compounds that do not present QT liabilities. These strategies can differ according to the pharmaceutical class, while experimental models differ according to the stage of development of the compound. Several in vitro models are employed in discovery (radioligand binding, high-throughput patch clamp, efflux, and fluorescence assays). These models, coupled with in silico methods, allow companies to screen a high number of compounds. Other in vitro models, applied later in the R&D process (action potential duration, APD, in Purkinje fibers or papillary muscle and the isolated heart) are useful in better describing the activity of compounds on cardiac ion channels. The most robust and accepted in vivo test is represented by telemetry studies in conscious non-rodents.
Arrigoni
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Nerviano Medical Sciences, Preclinical Development/Experimental ADMET/Safety Pharmacology, Nerviano, Italy. Caludio.Arrigoni@nervianoms.com
Crivori
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D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects* / Q000503:physiopathology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D023421:Models, Animal; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology