Assessing proarrhythmic potential of drugs when optimal studies are infeasible

Rock, Edwin P.; Finkle, John K.; Fingert, Howard; Booth, Brian; Garnett, Christine; Grant, Stephen; Justice, Robert; Kovacs, Richard J.; Kowey, Peter R.; Rodríguez, I.; Sanhai, Wendy R.; Strnadova, Colette; Targum, Shari L.; Tsong, Yi; Uhl, Kathleen; Stockbridge, Norman

doi:10.1016/j.ahj.2009.02.020

Cited by 77 publications

(73 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Model (11) was implemented in NONMEM according to the FOCE method with interaction. Log-normal distributions were assumed for all the model parameters and an additive error model was considered.…”

Section: In Vitro Analysis Herg Current Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Marostica

Ammel²,

Teisman³

et al. 2015

J Pharmacokinet Pharmacodyn

View full text Add to dashboard Cite

Safety pharmacology studies are performed to assess whether compounds may provoke severe arrhythmias (e.g. Torsades de Pointes, TdP) and sudden death in man. Although there is strong evidence that drugs inducing TdP in man prolong the QT interval in vivo and block the human ether-a-go-go-related gene (hERG) ion channel in vitro, not all drugs affecting the QT interval or the hERG will induce TdP. Nevertheless, QT-interval prolongation and hERG blockade currently represent the most accepted early risk biomarkers to deselect drugs. An extensive pharmacokinetic/pharmacodynamic (PK/PD) analysis is developed to understand moxifloxacin's-induced effects on the QT interval by comparing the relationship between results of an in vitro patch-clamp model to in vivo models. The frequentist and the fully Bayesian estimation procedures were compared and provided similar performances when the best model selected in NONMEM is subsequently implemented in WinBUGS, which guarantees a straightforward calculation of the probability of QT-interval prolongation greater than 2.5 % (10 ms). The use of the percent threshold to account for the intrinsic differences between species and a new calculation of the probability curve are introduced. The concentration providing the 50 % probability indicates that dogs are more sensitive than humans to QT-interval prolongation. However, based on the drug effect, a clear distinction between species cannot be made. An operational PK/PD model of agonism was used to investigate the relationship between effects on the hERG and QT-interval prolongation in dogs. The proposed analysis contributes to establish a translational relationship that could potentially reduce the need for thorough QT studies.

show abstract

Section: In Vitro Analysis Herg Current Inhibitionmentioning

confidence: 99%

“…Further, apart from the ethical aspect, it is hard to scrutinize these incidences in humans in much detail. Nevertheless, although not all drugs that provoke a QT-interval prolongation cause TdP, drug-induced QT-interval prolongation represents an early risk biomarker for which a thorough and improved understanding is required [10,11].…”

Section: Introductionmentioning

confidence: 99%

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Marostica

Ammel²,

Teisman³

et al. 2015

J Pharmacokinet Pharmacodyn

View full text Add to dashboard Cite

show abstract

“…If approved, the drug's labeling will carry information concerning its degree of QT ⁄ QTc prolongation. 48,49 With the exception of a relatively small number of test drugs for which a classical TQT study is not feasible 50 (and for which the most thorough evaluation feasible still must be conducted), the TQT can be meaningfully regarded as a ''one study fits all'' scenario. However, several considerations suggest that a similarly styled ''Thorough BP Study'' (TBP study) would not be appropriate in the current context.…”

Section: Consideration Of An Existing Regulatory Landscapementioning

confidence: 99%

Assessing Blood Pressure Responses to Noncardiovascular Drugs: The Beneficial Role of Ambulatory Blood Pressure Monitoring

O’Brien

Turner

2012

J of Clinical Hypertension

View full text Add to dashboard Cite

It has become apparent that noncardiovascular drugs can affect blood pressure (BP) in an off-target manner, either by raising or lowering pressure or by negating the beneficial hypotensive effect of concomitantly prescribed antihypertensives. This paper presents compelling evidence that ambulatory blood pressure monitoring (ABPM) should be used to detect BP effects during the development of noncardiovascular drugs. The requirements for standardizing ABPM to obtain the most information from the least number of participants and the many advantages of obtaining a 24-hour BP profile are discussed. The use of ABPM in trials of antihypertensive agents, though differing in purpose (the demonstration of BP-lowering efficacy) from the use of ABPM in trials of noncardiovascular drugs (the demonstration of any off-target effect on BP) nonetheless provides methodological similarities that can be applied in both contexts with advantage. The paper also considers whether there are lessons to be learned from a regulatory science approach that is designed to prospectively identify unacceptable off-target cardiac effects of noncardiac drugs and offers some thoughts on how a future paradigm of standardized use of ABPM to assess off-target BP effects during the development of noncardiovascular drugs might benefit patient safety. J Clin Hypertens (Greenwich). 2013; 15:55-62. Ó2012 Wiley Periodicals, Inc.It has become clear that noncardiovascular drugs can raise or lower blood pressure (BP) in an off-target manner. The clinical relevance of small and transient, off-target drug-induced changes in BP to symptomatology, morbidity, or mortality is not known because the subject has not been systematically studied. However, Grossman and Messerli 1 recently observed that ''severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported.'' Off-target BP responses have therefore garnered increasing scientific and regulatory interest in recent years, being addressed at various conferences and in the literature (Table). 14,15Considerable attention is now being paid to designing an appropriately informative assessment strategy that can be employed in noncardiovascular drug development programs to prospectively identify such BP responses.While increases will likely attract more attention, decreases of certain magnitudes are also undesirable, particularly in some patient populations. Additionally, interactions between noncardiovascular drugs and antihypertensives that may either negate or potentiate hypotensive efficacy have received little study to date, but it can be reasonably assumed that many drugs either reduce or potentiate the BP-lowering effect of antihypertensive medication. For example, Grossman and Messerli 1 noted that rifampicin, a bactericidal antibiotic that induces CYP3A4 and P-glycoprotein, considerably reduces the plasma concentrations and the renin-inhibiting effect of aliskiren and some calcium antagonists by decreasing oral bioavailability. Sitagliptin, a dipeptidyl peptidase-IV inhibit...

show abstract

“…In this often immune-compromised and severely ill patient population, it is difficult to justify the use of placebo and an antibiotic (the positive control, moxifloxacin), and many ECG studies with oncology agents in cancer patients are therefore uncontrolled (Lesimple et al 2013) and frequently powered to exclude a somewhat larger effect (around 20 ms) than TQT studies in healthy subjects (Bello et al 2007;Graham et al 2013;Rock et al 2009;Sarapa and Britto 2008). Apart from these limitations, other elements from the TQT study design, such as strictly controlled experimental conditions, serial ECGs at baseline, and post-dosing, are implemented to the extent feasible into ECG studies in oncology patients (Rock et al 2009). A large number of tyrosine kinase inhibitors with indications in oncology have recently been approved or are in clinical development, and this class of drugs can illustrate the different approaches taken in terms of definitive ECG assessment (Shah et al 2013).…”

Section: Ecg Assessment With Oncology Drugsmentioning

confidence: 99%

Clinical ECG Assessment

Darpö

2015

Principles of Safety Pharmacology

View full text Add to dashboard Cite

With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

show abstract

Assessing proarrhythmic potential of drugs when optimal studies are infeasible

Cited by 77 publications

References 32 publications

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

Assessing Blood Pressure Responses to Noncardiovascular Drugs: The Beneficial Role of Ambulatory Blood Pressure Monitoring

Clinical ECG Assessment

Contact Info

Product

Resources

About