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Concentration-QT Relationships Play a Key Role in the Evaluation of Proarrhythmic Risk During Regulatory Review

From the Pharmacometrics Staff, Office of Clinical Pharmacology (Dr Garnett, Dr Bhattaram, Dr Jadhav, Dr Madabushi, Dr Tornøe, Dr Wang, Dr Zhu, Dr Gobburu) and the Division of Cardiovascular and Renal Drug Products (Dr Beasley, Dr Stockbridge), Center of Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.

The criterion for assessing whether a drug prolongs QT as described in the International Conference on Harmonization topic E14 guideline does not explicitly account for individual drug concentrations. The authors' experience with reviewing QT studies indicates that understanding the relationship, if any, between individual drug concentration and QT change provides important additional information to support regulatory decision making. Therefore, regulatory reviews of "thorough QT" studies routinely include a characterization of the concentration-QT relationship. The authors provide examples to illustrate how the concentration-QT relationship has been used to plan and interpret the thorough QT study, to evaluate QT risk for drugs that have no thorough QT studies, to assess QT risk in subpopulations, to make dose adjustments, and to write informative drug labels.

Key Words: Pharmacokinetics • pharmacodynamics • modeling • QT interval • ICH E14

Address for reprints: Christine E. Garnett, PharmD, Office of Clinical Pharmacology, OTS/CDER/FDA, 10903 New Hampshire Ave, Silver Spring, MD 20903-0002; e-mail: christine.garnett{at}fda.hhs.gov.

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