Thorough QT Study Research Articles

Should You Run a Dedicated TQT Study? Sponsor and Regulatory Considerations on Substitution Pathways to Assess QT Liability.

Cardiac safety regulatory guidance for drug development has undergone several monumental shifts over the past decade as technological advancements, analysis models and study best practices have transformed this landscape. Once, clinical proarrhythmic risk assessment of a new chemical entity (NCE) was nearly exclusively evaluated in a dedicated thorough QT (TQT) study. However, since the introduction of the International Council for Harmonisation (ICH) E14/S7B Q&A 5.1 and 6.1 TQT substitutions, drug developers are offered an alternative pathway to evaluate proarrhythmic risk during an ascending dose study in healthy volunteers or during a powered patient study, respectively. In addition, the findings as well as the manner in which nonclinical studies are conducted (i.e., utilizing best practices) can dictate the need for a positive control in the clinical study and/or affect the labeling outcome. Drug sponsors are now faced with the option of pursuing a dedicated TQT study or requesting a TQT substitution. Potential factors influencing the choice of pathway include the NCE mechanism of action, pharmacokinetic properties, and safety profile, as well as business considerations. This tutorial will highlight the regulatory framework for integrated arrhythmia risk prediction models to outline drug safety, delineate potential reasons why a TQT substitution request may be rejected and discuss when a standalone TQT is recommended.

Unbiased and efficient estimation of causal treatment effects in crossover trials.

We introduce causal inference reasoning to crossover trials, with a focus on thorough QT (TQT) studies. For such trials, we propose different sets of assumptions and consider their impact on the modeling strategy and estimation procedure. We show that unbiased estimates of a causal treatment effect are obtained by a g-computation approach in combination with weighted least squares predictions from a working regression model. Only a few natural requirements on the working regression and weighting matrix are needed for the result to hold. It follows that a large class of Gaussian linear mixed working models lead to unbiased estimates of a causal treatment effect, even if they do not capture the true data-generating mechanism. We compare a range of working regression models in a simulation study where data are simulated from a complex data-generating mechanism with input parameters estimated on a real TQT data set. In this setting, we find that for all practical purposes working models adjusting for baseline QTc measurements have comparable performance. Specifically, this is observed for working models that are by default too simplistic to capture the true data-generating mechanism. Crossover trials and particularly TQT studies can be analyzed efficiently using simple working regression models without biasing the estimates for the causal parameters ofinterest.

The new S7B/E14 Q&A document provides additional opportunities to replace the thorough QT study.

Since 2015, concentration-QTc analysis can be used to exclude that a drug has a concerning effect on the QTc interval. This has enabled replacing the designated TQT study by implementation of serial ECGs into routine clinical pharmacology studies, such as the First-in-Human (FIH) study. This has led to an increased proportion of FIH studies with this added objective of QT evaluation with the intention of replacing the TQT study. With the more recent, February 2022 revision of the S7B/E14 Q&A document, nonclinical assays/studies can be brought into the process of regulatory decisions at the time of marketing application. If the hERG and the non-rodent in vivo study are conducted according to described best practices, the previous requirement that a QTc effect > 10 ms must be excluded in healthy subjects at plasma concentrations 2-fold above what can be seen in patients can be reduced to covering concentrations seen in patients. For drugs that cannot be safely given in high doses to healthy subjects, ECG evaluation is often performed at the therapeutic dose in patients. If a QTc effect > 10 ms can be excluded, an argument can be made that the drug should be considered as having a low likelihood of proarrhythmic effects due to delayed repolarization. In this article, we describe what clinicians involved in early clinical development need to understand in terms of the hERG and in vivo studies to determine whether these meet best practices and therefore can be used in an integrated clinical/nonclinical QT/QTc risk assessment. This article is protected by copyright. All rights reserved.

Comparison of validity of standard nonclinical group size selection versus standard clinical group sizes for nonhuman primate QTc prolongation evaluation

The number of animals used in a nonhuman primate (NHP) in vivo QTc assessment conducted as part of the safety pharmacology (SP) studies on a potential new drug is relatively small (4–8 subjects). The number is much smaller than the number of healthy volunteers in a conventional thorough QT (TQT) study (40–60 volunteers). How is it possible that such small studies could offer an equivalent sensitivity in an integrated nonclinical and clinical cardiac repolarization risk assessment?This study provided the opportunity to empirically demonstrate in a large number of NHPs the performance of a nonclinical evaluation at a similar size to a TQT study.By contrasting an analysis mimicking the sampling and aggregation of QTc interval data in a manner which is TQT-like with a more conventional SP-like analysis it was demonstrated that the SP-like analysis was more sensitive. In prospective power calculations 80% power at p = 0.05 can be achieved for a 5 ms QTc change with only n = 8 NHPs using the SP-like analysis and in a group of only 4 NHPs 80% power to detect 10 ms could be achieved. By contrast groups of 24 NHPs would be required to achieve 80% power to detect 5 ms using the TQT-like sampling and aggregation approach.Overall, this study has demonstrated that smaller safety pharmacology in vivo QTc assessments using all the available data in larger data aggregates can achieve sensitivity comparable to a human TQT study.

Characterisation of the Cardiovascular Effects of a Meal: QTcF Assessment and Further Insights into the Physiological Effects

The electrical activity of the heart, characterised by the QT interval on an electrocardiogram (ECG), serves as a crucial parameter for evaluating cardiac health. Variations in the QT interval, particularly when corrected for heart rate using Fridericia's formula (QTcF), have long been of interest in cardiology and play a pivotal role in assessing cardiac safety in clinical trials. Understanding the influence of meals given at different times on QTcF intervals is essential for the accurate execution of Thorough QT (TQT) studies. Moreover, it has been proposed that this meal-related QT interval shortening could serve as a valuable indicator of assay sensitivity in TQT studies or even as a potential integration of TQT investigations into in Phase I/II studies. This study explores the impact of meals on QTcF intervals, specifically in the context of pharmacodynamic studies and TQT investigations. The primary goal is to gain insights into how different meals and baseline calculations affect QTcF changes and their potential implications for cardiac health and the risk of arrhythmias. Recent research has begun shedding light on the intricate relationship between meal composition, timing, and QTcF alterations. Several studies have investigated the effects of various nutrients, such as carbohydrates, fats, and proteins, on QTcF duration, as well as the implications of postprandial changes. These investigations have unveiled the complex interplay between dietary components and the cardiovascular system, raising essential questions about how our dietary choices may influence cardiac electrophysiology. In this comprehensive meta-analysis, we analyse data from nine studies, all conducted in accordance with Good Clinical Practice and ethical standards. These studies were approved by Ethics Committees and Regulatory authorities. Our analysis focuses on ECG assessments, involving the use of 12-lead ECGs recorded electronically and evaluated by certified cardiologists. We apply the Fridericia formula for QT correction (QTcF), as it has been shown to provide more accurate results across different heart rates compared to other correction methods. Our findings confirm existing literature into the impact of meals on QTcF intervals. We observe a consistent shortening of QTcF following breakfast, exceeding 5 milliseconds, which aligns with the positive control requirement defined by ICH E14, thus demonstrating the validity of our approach. In contrast, the effect of lunch is consistently less than 5 milliseconds across various timepoints and studies, indicating differences in the meal-related QTcF changes. Furthermore, our analysis incorporates gender-based assessments, showing that women exhibit a smaller effect than men, which is significant for breakfast and the fasted condition. These results suggest that the observed QTcF effect post-breakfast is a combination of the meal itself and factors unique to the initial day of a study. This insight holds potential for improving the design and interpretation of cardiac safety studies, particularly in Phase I investigations, and may offer the opportunity to explore the removal of positive control agents like Moxifloxacin, thereby reducing exposure to harmful challenge agents and contributing to the global effort to combat antimicrobial resistance (AMR). In conclusion, this meta-analysis advances our understanding of meal-induced QTcF changes and their significance in cardiac safety assessment, offering the prospect of more efficient and patient-focused drug development practices. This not only contributes to enhanced safety but also supports the reduction of antibiotic consumption, a key element in the global fight against AMR.

ECG Evaluation as Part of the Clinical Pharmacology Strategy in the Development of New Drugs: A Review of Current Practices and Opportunities Based on Five Case Studies.

The International Conference on Harmonization (ICH) E14 document was revised in 2015 to allow concentration-corrected QT interval (C-QTc) analysis to be applied to data from early clinical pharmacology studies to exclude a small drug-induced effect on QTc. Provided sufficiently high concentrations of the drug are obtained in the first-in-human (FIH) study, this approach can be used to obviate the need for a designated thorough QT (TQT) study. The E14 revision has resulted in a steady reduction in the number of TQT studies and an increased use of FIH studies to evaluate electrocardiogram (ECG) effects of drugs in development. In this review, five examples from different sponsors are shared in which C-QTc analysis was performed on data from FIH studies. Case1 illustrates a clearly negative C-QTc evaluation, despite observations of QTc prolongation at high concentrations in nonclinical studies. In case2 C-QTc analysis of FIH data was performed prior to full pharmacokinetic characterization in patients, and the role of nonclinical assays in an integrated risk assessment is discussed. Case3 illustrates a positive clinical C-QTc relationship, despite negative nonclinical assays. Case4 demonstrates a strategy for characterizing the C-QTc relationship for a nonracemic therapy and formulation optimization, and case5 highlights an approach to perform a preliminary C-QTc analysis early in development and postpone the definitive analysis until proof of efficacy is demonstrated. The strategy of collecting and storing ECG data from FIH studies to enable an informed decision on whether and when to apply C-QTc analysis to obviate the need for a TQT study is described.

How to Successfully Generate an Alternative Approach to a Thorough QT Study: GLPG1972 as an Example.

During development of a drug, the requirement of evaluating the proarrhythmic risk and delayed repolarization needs to be fulfilled. Would it be possible to create an alternative to a thorough QT (TQT) study or is there a need to perform a dedicated TQT study? How is an alternative approach generated, what information is available, and which instructions are considered missing today to generate such an approach? This tutorial describes the considerations and path followed to create an early and feasible alternative to a TQT study using experience-based insights from a successful application to the US Food and Drug Administration for GLPG1972, an ADAMTS-5 inhibitor, and discusses the approach used in light of the current guidelines and literature.

Four-Way Crossover Phase 1 Thorough QT Study to Assess Cardiac Safety of Domperidone and Consideration for Design and Conduct of QT/QTc Study in China.

This study aimed to evaluate the QT prolongation potential of domperidone in healthy Chinese participants and explore the possibility of a thorough QT (TQT) study in China with a smaller sample size using concentration-QT (C-QT) modeling. Part 1 was a randomized, placebo- and positive-controlled, multiple-dose, 4-way crossover TQT study in healthy Chinese participants; 44 participants were randomized to either domperidone 10/20mg or placebo 3 times daily, on days 1 to 3, followed by a single dose of either 10/20mg domperidone/domperidone-placebo/domperidone-placebo plus 400mg of moxifloxacin, on day 4. Twelve-lead electrocardiograms were recorded in triplicate at predefined time points with pharmacokinetic sampling. The results were that change from baseline in QT interval corrected for heart rate (QTc) using the Fridericia formula (QTcF) between domperidone and placebo was 1.3milliseconds and 2.7milliseconds for 10 and 20mg 3 times daily, and upper limits of 2-sided 90%CI for all time points were below regulatory threshold of 10milliseconds. In part 2, resampling analysis using C-QT modeling for moxifloxacin showed false-negative rates of <5% with sample sizes ≥6. We could conclude that no clinically relevant effect on corrected QT interval or new safety signals was observed with domperidone. A dedicated TQT study with C-QT modeling could assess drug effects on QT/corrected QT intervals for novel drug development in China.

The Challenges of Predicting Drug-Induced QTc Prolongation in Humans.

The content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.

Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects.

Perhexiline has been used to treat hypertrophic cardiomyopathy. In addition to its effect on carnitine-palmitoyltransferase-1, it has mixed ion channel effects through inhibition of several cardiac ion currents. Effects on cardiac ion channels expressed in mammalian cells were assayed using a manual patch-clamp technique, action potential duration (APD) was measured in ventricular trabeculae of human donor hearts, and electrocardiogram effects were evaluated in healthy subjects in a thorough QT (TQT) study. Perhexiline blocked several cardiac ion currents at concentrations within the therapeutic range (150-600 ng/mL) with IC50 for hCav1.2 ∼ hERG < late hNav1.5. A significant APD shortening was observed in perhexiline-treated cardiomyocytes. The TQT study was conducted with a pilot part in 9 subjects to evaluate a dosing schedule that would achieve therapeutic and supratherapeutic perhexiline plasma concentrations on days 4 and 6, respectively. Guided by the results from the pilot, 104 subjects were enrolled in a parallel-designed part with a nested crossover comparison for the positive control. Perhexiline caused QTc prolongation, with the largest effect on ΔΔQTcF, 14.7milliseconds at therapeutic concentrations and 25.6milliseconds at supratherapeutic concentrations and a positive and statistically significant slope of the concentration-ΔΔQTcF relationship (0.018 milliseconds per ng/mL; 90%CI, 0.0119-0.0237 milliseconds per ng/mL). In contrast, the JTpeak interval was shortened with a negative concentration-JTpeak relationship, a pattern consistent with multichannel block. Further studies are needed to evaluate whether this results in a low proarrhythmic risk.

The New S7B/E14 Question and Answer Draft Guidance for Industry: Contents and Commentary.

In August 2020, the International Council on Harmonisation (ICH) released a new draft document, which for the first time combined nonclinical (S7B) and clinical (E14) Questions and Answers (Q&As) into 1 document. FDA describes the revision as a “value proposition”: if the human ether‐à‐go‐go assay and the in vivo study are performed in a standardized way, the number of dedicated thorough QT (TQT) studies can be reduced. In this article, we describe and discuss the Q&As that relate to clinical ECG evaluation. If supported by negative standardized nonclinical assays, Q&A 5.1 will obviate the need for a TQT study in the case that a >2‐fold exposure margin vs high clinical scenario cannot be obtained. Q&A 6.1 addresses drugs that are poorly tolerated in healthy subjects and cannot be studied at high doses or in placebo‐controlled studies; it therefore mainly applies to oncology drugs. It will enable sponsors to claim that a new drug has a “low likelihood of proarrhythmic effects” in the case that the mean corrected QT effect is <10 milliseconds at the time of market application. The E14 2015 revision allowed application of concentration–corrected QT analysis on data from routinely performed clinical pharmacology studies, for example, the first‐in‐human study and the proportion of dedicated TQT studies has since steadily decreased. It can be foreseen that the proposed new revision will further reduce the number of TQT studies. To achieve harmonization across regulatory regions, it seems important to reach consensus within the International Council on Harmonisation group on the new threshold proposed in 6.1. For this purpose, the Implementation Working Group has asked for public comments.

QT Prolongation Risk Assessment in Oncology: Lessons Learned From Small-Molecule New Drug Applications Approved During 2011-2019.

The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug to delay cardiac repolarization (QT prolongation), including general guidelines for cases in which a conventional thorough QT study (TQT) might not be feasible. These guidelines have been updated through the ICH question-and-answer process, with the last revision in 2015. We conducted a comprehensive analysis of QT prolongation evaluation of small-molecule new drug applications (NDAs) approved in oncology between 2011 and 2019 to extract learning experience. The following information was analysed: (1) methods to assess QT prolongation, (2) electrocardiogram data collection, (3) QT-related label language, and (4) postmarketing requirements. Overall, every NDA included a QT assessment. The concentration-QTc modeling approach (studies in which QT was not the primary objective) was the most common approach (59%), followed by the TQT and the dedicated QT studies (20% and 21%, respectively). The quality and quantity of the QT assessments were different across NDAs, which suggested relatively large flexibility in the designs and approaches to characterizing QT liability. The QT-related label language reflected the QT results, but also the safety events and the study design limitations because of the oncology settings. There was no delay in approval because of less robust QTc studies as long as the benefit-to-risk ratio of the drug was acceptable, and the implications were reflected in the label. This work offers a structured understanding of the QT evaluation criteria by the Food and Drug Administration and can assist in planning QT prolongation assessments in oncology settings.

Relationship between antofloxacin concentration and QT prolongation and estimation of the possible false-positive rate

PurposeTo elucidate the relationship between antofloxacin (AT) plasma concentration and QT interval prolongation, compare the effects of different correction and analytical methods on conclusions, and estimate the possible false-positive rate in thorough QT (TQT) studies. MethodsTwenty-four healthy Chinese volunteers from a four-period crossover TQT study orally received 200 mg/d AT, 400 mg/d AT, 400 mg/d moxifloxacin, and a placebo in a random order for 5 d for each. QT interval samples were collected on d 1 and d 5. Population models were established describing the relationship between QT and AT concentration. The yardstick from ICH E14 guidelines was used to measure the effect of drugs on QT prolongation both in biostatistical and modeling analyses. A possible false-positive rate was estimated by constructing a 1000-time bootstrap to obtain the rate-of-difference values between d 1 and d 5 over 5 ms in the placebo period. ResultsIn the modeling analysis, the QT prolongation estimate at the mean maximal concentration of AT (4.51 μg/mL) was 3.84 ms, and its upper bound of the one-sided 95 % CI was 7.04 ms, which showed a negative effect on QT interval prolongation. The estimation for the false-positive rate was 31 % in this study. ConclusionThe effect of AT on QT interval prolongation may not have been significant at the dosage of 400 mg. Baseline and placebo adjustments were necessary in TQT studies. Population modeling has demonstrated clear superiority in making full use of data to accurately analyze the relationship between drugs and QT intervals.

QT assessments in oncology drug development and related labels.

e14127 Background: A thorough QT (TQT) study, designed to evaluate whether a new drug excludes a small mean increase in the QTc interval (i.e., &gt; 10 ms) which is considered to have low proarrhythmic risk, is often not feasible for oncology drugs. Alternative designs that assess the QTc changes in cancer patients are used to exclude large mean increases (i.e., &gt; 20 ms) for drugs where the expected benefit outweighs the small proarrhythmic risk. A retrospective analysis was conducted to evaluate QT study designs and the consistency of QT labeling for oncology drugs. Methods: This analysis included FDA approved oncology drugs with QT studies reviewed by CDER’s Interdisciplinary Review Team as of 10/01/2019. Information collected included the clinical study design (i.e., TQT, alternative designs such as a sub-study in a Phase 2/3 trial), primary analysis (i.e., central tendency or concentration-QTc [CQT] analysis), QT findings at the therapeutic dose (i.e., the mean [M] and the upper bound of 90% confidence interval [UCI] of QTc changes), supportive data (i.e., nonclinical cardiac safety data, if applicable), conclusion of the QT assessment, and labeling statements in Section 12.2 (Pharmacodynamics) and Section 5 (Warnings &amp; Precautions) of the product labels. Baseline QTc values in these alternative studies were compared to those in TQT studies across different therapeutic areas. Results: The analysis included 72 oncology drugs. The mean baseline QTc value is 411.2 ms in male patients (n = 6951) and 394.6 ms in male healthy volunteers (n = 22288), and 414.3 ms in female patients (n = 6412) and 408.8 ms in female healthy volunteers (n = 15682). Alternative study designs were used for 63 (87.5%) drugs while TQT study was only used for 9 (12.5%) drugs. CQT was used as the primary analysis for 11 (15.3%) drugs. Among the 72 product labels, 8 labels do not have QT information in Section 12.2 and 9 labels inconsistently describe the results of an alternative study. Warnings and Precautions for QT Prolongation in Section 5 of the labels were triggered by positive signals in the QT assessment or clinical trial safety monitoring experience. Conclusions: Cancer patients had higher QTc and less sex difference at baseline than healthy volunteers. QT labeling consistency in Section 12.2 could be improved by standardizing the description of study results based on QT study designs. Disclaimer: The contents reflect the views of the authors and should not be construed to represent the FDA's views or policies.

Real estate diagrams: A tool to quickly assess the utility of a new predictive technology

IntroductionScientists are increasingly in a position to ask whether or not to adopt new technologies. We present a visualization tool to help scientists swiftly evaluate the worth of new assays. MethodsThe parameters (prevalence, sensitivity and, specificity) relevant to use of a toxicity test have values between 0 and 1. The proper arrangement of the parameters can be used to define areas in a [0,1] × [0, 1] cross-space. Our analogy is a square plot of land subdivided into smaller lots. We call the resultant graphic a real estate diagram. ResultsWe use the well studied example of predicting prolongation of the QT interval of the electrocardiogram to illustrate the diagrams. The experience in human clinical Thorough QT (TQT) studies has been described (Park et al., 2013). Within the data we chose two chronological sets: 2 blocks of two years (2005–2006 and 2011–2012). In the first block 13 of 29 (45%) submitted compounds had positive TQT studies; in the second block the prevalence was 4 of 42 (10%). In other studies, the hERG channel patch-clamp assay used in predicting TQT outcome had an expected sensitivity of 0.70 and expected specificity of 0.72. Real estate diagrams were constructed to yield insight into the positive and negative predictive value (PPV and NPV, respectively) of the TQT prediction. The structure of the real estate diagrams revealed that increasing assay sensitivity in the face of declining prevalence would have a trivial effect on PPV and NPV. DiscussionNonclinical safety scientists will be called upon to question whether a new technology has the potential to meaningfully increase the predictive value of testing regimens. The real-estate diagram is a useful tool in making that assessment.

Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology

BackgroundGlycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting β2-agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI. MethodsThe thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere®), GFF MDI 144/38.4 and GP MDI 144 μg, compared with placebo MDI and open-label moxifloxacin 400 mg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6 μg compared with open-label FF dry powder inhaler (DPI; Foradil® Aerolizer®) 12 μg, in patients with moderate-to-severe COPD (PT003003 [NCT01349803]). ResultsSeventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144 μg all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6 μg did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12 μg. ConclusionsNo clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4 μg. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD.

Can early Phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature

Event Abstract Back to Event Can early Phase ECG assessment serve as an alternative for thorough QT studies? A review of the literature Pieter-Jan N. Berghmans1* and Nina Serluppens1 1 SGS, Life Science, Belgium Background: In Phase I research, we often deal with the question whether Early Phase Exposure-Response (ER) QT analysis can replace Late Phase Thorough QT (TQT) studies. In response we performed a review of available literature. Methodology: Literature study, 22 articles were selected for review. Results: TQT-studies are recommended (cfr. 2005 ICH E14 guidelines) to assess potential of drugs to prolong QT interval. These stand-alone and large, expensive studies are carried out in Later Phase drug development. Incorporating QT-effect measurements in Early Phase with an ER analysis could be an alternative enhancing cost-efficiency. Current literature provides promising evidence for this Early Phase ECG approach. Several trials including 1 compound; and 1 trial including 6 compounds (IQ-CSRC trial) , each managed to correctly categorize (QT prolonging/ no QT prolonging) every single compound using a Phase I setup and ER QT-analysis Furthermore, we identified key characteristics to enhance statistical power (in a cost-efficient way): • Sample size: ≥ 9 subjects with supra therapeutic dose, ≥ 6 placebo subjects (common in SAD)2 • Triplicate ECG in 5 min interval3 • 6-8 ECG timepoints first 24h post-dose4 • Enough ECG timepoints around Tmax Conclusions: Literature provides supporting evidence to replace TQT studies with Early Phase ECG assessment. These data suggest that compounds with a clean pre-clinical profile and a robust negative Early Phase ER analysis, can waive the request for a later phase TQT study.

The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative — Update on progress

The implementation of the ICH S7B and E14 guidelines has been successful in preventing the introduction of potentially torsadogenic drugs to the market, but it has also unduly constrained drug development by focusing on hERG block and QT prolongation as essential determinants of proarrhythmia risk. The Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative was established to develop a new paradigm for assessing proarrhythmic risk, building on the emergence of new technologies and an expanded understanding of torsadogenic mechanisms beyond hERG block. An international multi-disciplinary team of regulatory, industry and academic scientists are working together to develop and validate a set of predominantly nonclinical assays and methods that eliminate the need for the thorough-QT study and enable a more precise prediction of clinical proarrhythmia risk. The CiPA effort is led by a Steering Team that provides guidance, expertise and oversight to the various working groups and includes partners from US FDA, HESI, CSRC, SPS, EMA, Health Canada, Japan NIHS, and PMDA. The working groups address the three pillars of CiPA that evaluate drug effects on: 1) human ventricular ionic channel currents in heterologous expression systems, 2) in silico integration of cellular electrophysiologic effects based on ionic current effects, the ion channel effects, and 3) fully integrated biological systems (stem-cell-derived cardiac myocytes and the human ECG). This article provides an update on the progress of the initiative towards its target date of December 2017 for completing validation.

Can an early phase clinical pharmacology study replace a thorough QT study? Experience with a novel H3-receptor antagonist/inverse agonist.

The objective of the present study was to compare the effects of pitolisant on QTcF interval in a single ascending dose (SAD) study and a thorough QT (TQT) study. The SAD study at three dose levels of pitolisant enrolled 24 males and the TQT study at two dose levels 25 males. Both studies intensively monitored ECGs and pitolisant exposure. Effect on QTcF interval was analysed by Intersection Union Test (IUT) and by exposure-response (ER) analysis. Results from the two studies were compared. In both studies, moxifloxacin effect established assay sensitivity. IUT analysis revealed comparable pitolisant-induced maximum mean (90 % confidence interval (CI)) placebo-corrected increase from baseline (ΔΔQTcF) in both the studies, being 13.3 (8.1; 18.5) ms at 200-mg and 9.9 (4.7; 15.1) ms at 240-mg doses in SAD study and 5.27 (2.35; 8.20) ms at 120-mg dose in TQT study. ER analysis revealed that ER slopes in SAD and TQT studies were comparable and significantly positive (0.031 vs 0.027 ms/ng/mL, respectively). At geometric mean concentrations, bootstrap predicted ΔΔQTcF (90 % CI) were 9.23 (4.68; 14.4) ms at 279 ng/mL (240-mg dose) in the SAD study and 4.97 (3.42; 8.19) ms at 156 ng/mL (120-mg dose) in the TQT study. Pitolisant lacked an effect of regulatory concern on QTc interval in both the studies, however analysed, suggesting that the results from the SAD study could have mitigated the need for a TQT study. Our findings add to the growing evidence that intensive ECG monitoring in early phase clinical studies can replace a TQT study.

Clinical Pharmacology Profile of Pacritinib (PAC), a Novel JAK2/FLT3 Inhibitor

Introduction: PAC is a kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CFS1R that does not inhibit JAK1. PAC has demonstrated activity in phase (Ph) 1-3 clinical studies. Nonclinical and clinical pharmacokinetic (PK) and pharmacodynamic studies support a 400 mg QD oral dosing regimen in ongoing Ph 3 studies in myelofibrosis. Here we present PK data from a series of Ph 1 studies of PAC.Methods: Seven Ph 1 studies were conducted in healthy subjects receiving a single 100, 200, or 400 mg dose of PAC. In an ADME mass balance study, [14 C]-PAC was administered to characterize routes of disposition. Separate drug interaction studies were conducted to assess effects of a strong CYP3A4 inhibitor (clarithromycin) or strong pan-CYP450 inducer (rifampin) on PAC PK. Cardiac safety of PAC was evaluated in a thorough QT (TQT) study. Food-effect, dose proportionality, and relative bioavailability studies were also conducted.Results: 140 subjects across 7 studies received single doses of PAC 100-400 mg. PK parameters of PAC 400 mg are presented in the Table (n=12). Following administration of single 100-400 mg PAC doses under fasted conditions, systemic exposure increased in a linear, but less than dose proportional manner. Among identified metabolites, the 2 major metabolites (M1, M2) exhibit relatively low pharmacological potency and are unlikely to contribute to PAC activity. Following a 400 mg single dose of [14 C]-PAC, the parent compound was the predominant moiety in plasma. Mean radioactivity recovery in urine = 3.22% of administered dose with intact PAC excreted in urine = 0.12% of administered dose. Of all 9 metabolites formed, M7, a glucuronidated metabolite, was the predominant radioactive component (3.03% of administered dose) excreted in urine. Mean radioactivity recovery in feces = 85.46% of administered dose and M2 (O- dealkylation metabolite) was the predominant component (24.08% of administered dose). When co-administered with clarithromycin (CYP3A4 inhibitor), PAC exposure increased with mean Cmax and AUC approximately 1.3- and 1.8-fold higher, respectively, with a similar mean t1/2 vs PAC alone. Co-administration with rifampin, a strong CYP3A4 inducer, reduced mean PAC Cmax and AUC by 51% and 87%, respectively vs PAC alone. Median Tmax was similar when co-administered with rifampin vs PAC alone (5-6 h), but t1/2 was shortened by approximately 65% (PAC: 43.3 h; PAC + rifampin: 15.1 h). Administration of single oral doses of PAC 400 mg in a placebo- and moxifloxacin-controlled TQT study had no clinically relevant effects on ECG parameters, including heart rate. There was no effect on QT prolongation (mean QTcF change <10 msec) and a small but non-clinically significant shortening in the placebo-corrected change in QTcF below 0 msec in the first 12 h post-dose. Across all clinical pharmacology studies, PAC was tolerable (primarily grade 1 gastrointestinal AEs), consistent with the PAC clinical safety profile to date.Conclusions: PAC exhibits moderate oral bioavailability and is eliminated primarily through metabolism and biliary excretion. Minimal excretion occurs via renal clearance, indicating dosage adjustment is unlikely to be warranted in renal impairment. Increase in PAC exposure is limited when co-administered with a strong CYP3A4 inhibitor, unlikely necessitating dosage adjustments. There is marked reduction in systemic exposure when co-administered with a strong CYP450 inducer and co-administration should therefore be avoided due to potential for negative impact on efficacy. PAC was not found to cause QT prolongation, suggesting favorable cardiac safety. Single 100-400 mg doses of PAC were well tolerated in healthy volunteers in these studies. Overall, PAC exhibited a favorable clinical pharmacology profile supportive of its safety and tolerability at clinical dose levels.TablePK Parameter(Geometric Mean; n=12)PAC 400 mgCmax, μg/mL3.83AUC0-t, μg∙h/mL184t1/2, h37.5Tmaxa, h6.00λz, L/h0.0185CL/F, L/h2.08Vz/F, L112Oral bioavailability, %58.6aMedian for Tmax.λz, terminal elimination rate constant; AUC0-t, area under the plasma concentration curve from time 0 to time t; CL/F, apparent oral clearance; Cmax, maximum plasma concentration; t1/2, half-life; Tmax, time to maximum plasma concentration; Vz/F apparent volume of distribution during terminal phase. DisclosuresAl-Fayoumi:CTI Biopharma: Employment, Equity Ownership. Off Label Use: This abstract discusses off-label use of pacritinib. Campbell:CTI Biopharma: Equity Ownership. Amberg:BMS: Employment, Equity Ownership; Juno: Equity Ownership. Zhou:CTI Biopharma: Employment, Equity Ownership. Millard:CTI Biopharma Corp.: Employment. Dean:CTI Biopharma: Employment, Equity Ownership.