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Considerations for Clinical Trial Design and Data Analyses of Thorough QT Studies Using Drug‐Drug Interaction
Author(s) -
Zhu Hao,
Wang Yaning,
Gobburu Jogarao V.,
Garnett Christine E.
Publication year - 2010
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270009358710
Subject(s) - drug , drug drug interaction , medicine , drug trial , clinical trial , pharmacology , intensive care medicine
• J Clin Pharmacol 2010;50:1106-1111 T prolongation of the QT interval associated with polymorphic ventricular tachycardia or torsades de pointes (TdP) is one of the major reasons for market withdrawal of the approved drugs as described in a recent review. The proarrhythmic potential for non-antiarrhythmic drugs is expected to be evaluated in a thorough QT study (TQTS) as described in the International Conference on Harmonisation topic E14 (ICH E14) guideline. It is recommended that the test drug be assessed at supratherapeutic exposures, if not precluded by safety considerations. The supratherapeutic dose should cover the increase in drug and metabolite concentrations in the presence of intrinsic (eg, renal impairment, age, gender) and extrinsic (eg, metabolic inhibition, food effects) factors. Supratherapeutic concentrations are most commonly achieved by administering the test drug at substantial multiples of the highest intended clinical dose. This approach is not always feasible, especially for drugs that have saturable absorption. Alternatively, drug concentrations can be increased by maximally inhibiting metabolism by coadministering a potent metabolic inhibitor (eg, ketoconazole). With this approach, the primary endpoint would be the difference in baseline-adjusted QTc interval between the test drug plus inhibitor and placebo plus inhibitor. The underlying assumption is the inhibitor has no effect on the QT/QTc interval. If this assumption is not valid, then alternative approaches to the analysis would need to be considered. We present a blinded example of a TQTS submitted to the Food and Drug Administration (FDA), for which the sponsor plans to achieve supratherapeutic concentrations by incorporating metabolic inhibition. Major challenges for study design and traditional E14 data analysis are discussed. In addition, we describe a multivariate concentration-QTc model to assess the pharmacokinetic and potential pharmacodynamic interactions between the investigational drug and metabolic inhibitor to determine whether the investigational drug prolongs the QTc interval. To gain confidence in the model we applied, the validity of the structural model is discussed under different simple, yet likely, scenarios. The statistical evaluation of the concentration-QT model is beyond the scope of this article. We believe that this is the first report describing this modeling approach as applied to a TQTS.