Christine Garnett

Center for Drug Evaluation and Research

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Norman Stockbridge

United States Food and Drug Administration

Lars Johannesen

Center for Drug Evaluation and Research

Marek Malík

Imperial College London

José Vicente

Center for Drug Evaluation and Research

Börje Darpö

Clarion University

Katerina Hnatkova

Lung Institute

Georg Ferber

MetroHealth

Jogarao Gobburu

University of Maryland, College Park

David G. Strauss

United States Food and Drug Administration

Yaning Wang

Binzhou Medical University

Cooperative Institutions

University of Florida

246

Columbus Oncology and Hematology Associates

234

United States Food and Drug Administration

152

Center for Drug Evaluation and Research

139

Reckitt Benckiser (United States)

128

National Institutes of Health Clinical Center

Merck & Co., Inc., Rahway, NJ, USA (United States)

National Institutes of Health

John Wiley & Sons (United States)

University of Maryland, Baltimore

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Assessing electrocardiographic data quality and possible replacement of pharmacologic positive control in thorough QT/QTc studies by investigations of drug-free QTc stability

Heart Rhythm (2011)

Marek Malík Joanne Zhang Lars Johannesen Katerina Hnatkova Christine Garnett

Short QT syndrome

10.1016/j.hrthm.2011.06.016

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Citations (16)

Dealing with Global Safety Issues

Drug Safety (2013)

Norman Stockbridge Joel Morganroth Rashmi R. Shah Christine Garnett

Drug Development

Postmarketing surveillance

Value (mathematics)

10.1007/s40264-013-0016-z

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Citations (141)

Issue Information

The Journal of Clinical Pharmacology (2016)

Matthew K. Ito Raúl D. Santos Christopher J. White Mohammad Hejazi Faezeh Modarresi‐Ghazani

Aims and Scope: For more than 50 years, clinical pharmacologists, clinical and pharmaceutical researchers, drug development specialists, physicians, nurses, and other medical professionals have relied on The Journal of Clinical Pharmacology (JCP) for original research, special reviews, commentaries, and case reports on all phases of drug development from absorption, disposition, metabolism, excretion interactions, and preferred uses through post-marketing evaluations.

10.1002/jcph.870

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Citations (0)

Commentary on: “Levofloxacin‐Induced QTc Prolongation Depends on the Time of Drug Administration”

CPT Pharmacometrics & Systems Pharmacology (2016)

Christine Garnett Lars Johannesen

Circadian variations in the corrected QT (QTc) interval have been documented in clinical trials. Animal models show circadian variations in expression of the cardiac ion channels that are necessary to maintain the heart's electrophysiological properties. Can these diurnal rhythms in QTc affect the ability of a drug to delay cardiac repolarization?

Prolongation

Ventricular Repolarization

10.1002/psp4.12128

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Citations (3)

Experience in QT evaluation of oncology drug products since ICH E14 guidance

Journal of Clinical Oncology (2008)

Q. Liu Rajanikanth Madabushi Christine Garnett B Booth

2554 Background: The objective of a ‘thorough QT (TQT) study’ is to determine whether a drug at supratherapeutic concentrations has a pharmacological effect on cardiac repolarization as detected by QT/QTc prolongation. The design is a randomized, (preferably) double-blinded, placebo- and positive-controlled study typically conducted in healthy male and female volunteers. There are several challenges with implementing a TQT study for oncology drug products: toxicities preclude administering the drug at supratherapeutic concentrations to cancer patients or to healthy volunteers and it is not feasible to administer the positive control to cancer patients. Methods: NDAs submitted during 2006–2007 were reviewed for QT evaluation. The study design, analysis methods and labeling implications were compared across submissions. Lapatinib submission was used as a case study. Results: Nine original NDAs were submitted of which five have been approved, three are under-review and one was withdrawn. Seven (78%) of the submissions contained QT evaluation from phase 1/2 studies. Of the submissions with QT data, two submissions contained a dedicated QT study but these studies did not meet the criteria of a TQT study defined by ICH E14. Time-matched concentrations and ECGs were available in six (85%) of the seven submissions. Concentration-QT analysis was performed in all six submissions by FDA reviewers. Of the five approved submissions, four were found to prolong the QT interval and labeled accordingly. The lapatinib case study underlines the need for collecting useful and interpretable data when using alternative designs. Conclusions: It is important to assess QT prolongation of oncology drug products. A TQT should be conducted if the drug can be administered to healthy subjects or placebo controls can be used in patients. Alternative designs can be used to evaluate QT when TQT study cannot be conducted. However, strategic planning of the alternate designs early in development will aid in collecting useful, interpretable data. Studies employing time-matched baseline ECGs and time-matched concentrations are essential for assessing drug effects on QT interval when employing alternate designs. No significant financial relationships to disclose.

Lapatinib

10.1200/jco.2008.26.15_suppl.2554

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Citations (10)

Detection and impact of hysteresis when evaluating a drug’s QTc effect using concentration-QTc analysis

Journal of Pharmacokinetics and Pharmacodynamics (2020)

Georg Ferber Börje Darpö Christine Garnett Dalong Huang Dhananjay Marathe

Hysteresis

10.1007/s10928-020-09725-w

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Citations (4)

Issue Information

CPT Pharmacometrics & Systems Pharmacology (2017)

Piet van der Graaf Lena E. Friberg Stephen B. Duffull Douglas A. Lauffenburger Lang Li

10.1002/psp4.12123

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Citations (1)

Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study

Clinical Pharmacology & Therapeutics (2017)

José Vicente Robbert Zusterzeel Lars Johannesen Jay W. Mason Philip T. Sager

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a mechanistic‐based assessment of the proarrhythmic risk of drugs. CiPA proposes to assess a drug's effect on multiple ion channels and integrate the effects in a computer model of the human cardiomyocyte to predict proarrhythmic risk. Unanticipated or missed effects will be assessed with human stem cell‐derived cardiomyocytes and electrocardiogram (ECG) analysis in early phase I clinical trials. This article provides an overview of CiPA and the rationale and design of the CiPA phase I ECG validation clinical trial, which involves assessing an additional ECG biomarker (J‐Tpeak) for QT prolonging drugs. If successful, CiPA will 1) create a pathway for drugs with hERG block / QT prolongation to advance without intensive ECG monitoring in phase III trials if they have low proarrhythmic risk; and 2) enable updating drug labels to be more informative about proarrhythmic risk, not just QT prolongation.

hERG

Proarrhythmia

10.1002/cpt.896

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Citations (112)

Study Design Parameters Affecting Exposure Response Analysis of QT Data: Results From Simulation Studies

The Journal of Clinical Pharmacology (2018)

Georg Ferber Yaning Sun Börje Darpö Christine Garnett Jiang Liu

The operating characteristics of dose-escalating studies in terms of false-negative predictions of the QT effect and the power to exclude clinically relevant QT effects are not quantitatively established. One thousand single-ascending-dose (SAD) studies with 7 dose groups with 6/2 subjects on active drug/placebo were generated through simulation for each of 32 scenarios with (1) 8 different QT effects of the study drug and (2) achieved plasma concentration 2- or 4-fold above therapeutic levels. For each subject, drug-free QT data from a thorough QT study were subsampled to capture the circadian profile, on which a drug effect was added. The percentage of false-negative studies was between 4% and 9% when the drug's QT effect was set to 10 milliseconds. If a somewhat lower effect of 6.7 milliseconds was set at therapeutic concentrations, the fraction of negative studies was higher, 40% to 60% when the variability of the QT data was well controlled. When the QT effect was set to 5 milliseconds at therapeutic plasma concentrations, the power of SAD studies to exclude 10 milliseconds QT effect was generally above 70% (74% to 94%) with well-controlled QT variability, whereas the power was reduced to 36% to 69% if supratherapeutic plasma concentrations were not achieved. The rate of false-negative studies was acceptably low in placebo-controlled SAD studies. With a drug with no or a small QT effect, supratherapeutic plasma concentrations, and well-controlled variability of QT data, the power of SAD studies to exclude a relevant effect was above 70%.

10.1002/jcph.1065

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Citations (8)

Pulmonary Arterial Registry Risk Algorithms Improve Upon Clinical Trial Enrichment Methodology

Jacqueline V. Scott Manreet Kanwar Christine Garnett Norman Stockbridge Raymond L. Benza

10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2920

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Citations (1)