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OIII-A-2Performance characteristics of the analysis method for “thorough QT” studies in ICH E-14 by S CHAPEL; M HUTMACHER; M AGIN; L BENINCOSA; J FLEISHAKER; R LALONDE is a Medicine article available to read on EtoBox.

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BACKGROUND/AIMS: Drug-induced QT interval prolongation, which can lead to torsade de pointes, is a concern in drug development. The present study evaluated the predictability of nonclinical assays (in vitro hERG and in vivo safety pharmacology studies) for drug-induced QT interval prolongation. METHODS: Nonclinical and clinical data on 19 drugs/candidates were evaluated. Data included that submitted to the FDA in support of INDs and NDAs, and published data. Clinical studies included positive controlled QT studies and those showing QT interval prolongation without a positive control arm. Drugs were considered positive if the mean QTc increase was greater than 5 msec. Nonclinical criteria for a positive assay were: IC50 Յ1 M for hERG inhibition; 10% increase in QTc in vivo or significant at PϽ0.05. RESULTS: Of 10 drugs that were positive clinically (QTc increases of 5.5 to 62 ms), false negative rates were 50% and 60%, for hERG and in vivo studies, respectively. Of 9 drugs that were negative clinically, false positive rates were 22% and 14% for hERG and in vivo studies, respectively. For drugs positive in either hERG or in vivo studies, false negative and false positive rates were 2

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Author

S CHAPEL; M HUTMACHER; M AGIN; L BENINCOSA; J FLEISHAKER; R LALONDE

Publisher

Nature Publishing Group; Wiley (Blackwell Publishing); Wiley-Blackwell; Wiley; Springer Science and Business Media LLC; Research Square (ISSN 0009-9236)

Published

2006

Language

EN

Field

Medicine (Health Sciences)