concentration-QTc Research Articles

No QTc prolongation with CDK 4/6 inhibitor FCN-437c: results of a concentration-QTc analysis from a dedicated study in adult healthy subjects.

https://clinicaltrials.gov/study/NCT06290466?term=NCT06290466&rank=1, identifier [NCT06290466].

A phase I thorough QT/QTc study evaluating therapeutic and supratherapeutic doses of avacopan in healthy participants.

This phase I thorough QTc, double-blind, randomized, placebo- and positive-controlled, parallel group, multiple-dose study evaluated avacopan's effect on cardiac repolarization using concentration-QTc (C-QTc) as the primary analysis. Avacopan 30 mg b.i.d. (therapeutic dose) was administered orally on days 1 through 7 followed by avacopan 100 mg b.i.d. (supratherapeutic dose) on days 8 through 14 in 29 healthy participants. Moxifloxacin 400 mg and placebo were administered on days 1 and 15 in a nested crossover design for assay sensitivity in separate cohorts to 28 participants. Time-matched plasma concentrations and up to 10 replicate ECGs were obtained on prespecified days at baseline and postdose on days 1, 7, 14, and 15. The mean change from baseline on QTcF for avacopan (-5.5 to 3.5 ms) was similar to placebo (-6.9 to 1.4 ms) across days 1, 7, and 14. The mean effect on ΔΔQTcF (90% CI) was estimated as 1.5 ms (-0.17 to 3.09) and 0.8 ms (-2.41 to 4.05) for 30 and 100 mg avacopan b.i.d. treatments, respectively. Based on the C-QTc analysis, avacopan's effect on ΔΔQTcF >10 ms can be excluded within the observed plasma concentration range of up to ~1220 and ~335 ng/mL for avacopan and active major metabolite, M1, respectively. The estimated population slopes showed a shallow relationship, which was not statistically significant. There was no clinically meaningful effect of avacopan on heart rate or cardiac conduction (PR and QRS intervals). Avacopan appeared to be generally well tolerated in this study population.

Innovative approaches to cardiovascular safety pharmacology assessment

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM. As in prior years, the manuscripts reflect various areas of innovation in SP including in silico modeling of stroke volume, cardiac output and systemic vascular resistance, computational approaches that compare drug-induced proarrhythmic sensitivity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), an evaluation of the utility of the corrected J-Tpeak and Tpeak-to-Tend parameters from the ECG as potential proarrhythmia biomarkers, and the applicability of nonclinical concentration-QTc (C-QTc) modeling of data derived from the conduct of the in vivo QTc study as a component of the core battery of safety pharmacology studies.

Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure. A dedicated QTc study in patients with chronic coronary syndromes demonstrated no clinically relevant QTc effect of vericiguat for exposures across the therapeutic dose range (2.5-10 mg). Interval prolongation concentration-QTc (C-QTc) modeling was performed to complement the statistical evaluations of QTc in the dedicated QTc study. Individual time-matched, baseline- and placebo-corrected Fridericia-corrected QT interval values (ΔΔQTcF) were derived. Two approaches for ΔΔQTcF calculation were investigated: (1) ΔΔQTcF correction with data from a single baseline (as in the primary statistical analysis); and (2) ΔΔQTcF correction with a modeled baseline (considering all available individual non-treatment baselines). The ΔΔQTcF values were related to observed vericiguat concentrations with linear mixed-effects modeling. For both modeling approaches, a positive relationship was found between ΔΔQTcF and vericiguat concentration; however, the slope for the single-baseline approach was not statistically significant, whereas the slope from the modeled-baseline approach was statistically significant. The upper bound of the two-sided 90% confidence interval for model-derived QTc was <10 ms at the highest observed exposure (745 μg/L; investigated dose range 2.5-10 mg). By applying a single-baseline approach and a modeled-baseline approach that integrated all available QTc data across doses to characterize the QTc prolongation potential, this study showed that vericiguat 2.5-10mg is not associated with clinically relevant QTc effects, in line with the conclusion from the primary statistical analysis. ClinicalTrials.gov NCT03504982.

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.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting. In this work, a spline-based correction method (QTcSPL) was explored to mitigate the impact of HR changes in giredestrant C-QTc analysis. Giredestrant is a selective estrogen receptor degrader being developed for the treatment of patients with estrogen receptor-positive (ER+) breast cancer. A dose-related HR decrease has been observed in patients under giredestrant treatment, with significant reductions (>10bpm) observed at supratherapeutic doses. The QTcSPL method demonstrated superior functionality to reduce the correlation between QTc and HR as compared with the Fridericia correction (QTcF). The effect of giredestrant exposure on QTc was evaluated at the clinical dose of 30 mg and supratherapeutic dose of 100 mg based on a prespecified linear mixed effect model. The upper 90% confidence interval of ΔQTcSPL and ΔQTcF were below the 10ms at both clinical and supratherapeutic exposures, suggesting giredestrant has a low risk of QT prolongation at clinically relevant concentrations. This work demonstrated the use case of QTcSPL to address HR confounding challenges in the context of oncology drug development for the first time.

1283. Safety, Tolerability, and Pharmacokinetics of BRII-778, A Modified-Release Oral Formulation of Rilpivirine in Healthy Adult Subjects

Abstract Background BRII-778 is a modified release (MR) formulation of rilpivirine for once-weekly (QW) oral administration. BRII-778 aims to prolong oral absorption, lower Cmax, relatively, and reduce peak to trough ratio achieved with a MR formulation of rilpivirine, within the known efficacy and safety bounds established by once daily oral administration of rilpivirine. QW BRII-778 dosing may have advantages over once daily rilpirvirine in terms of patient convenience, and treatment adherence. Multiple MR formulations of rilpivirine were evaluated in healthy adult subjects in this Phase 1 study. Methods This was a Phase 1, randomized, double-blinded, placebo-controlled, study of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts, evaluating the safety, tolerability, and PK of BRII-778. Three MR formulations of rilpivirine, BRII-778-A1, -A2, and -A3, were evaluated in this study. Rilpivirine PK profiles after single or multiple doses of the three BRII-778 formulations were characterized under the fed state over the dose range of 150 mg to 750 mg. Food effect was assessed after a single oral dose of BRII-778-A3 750 mg. Exploratory concentration-QTc (C-QTc) analysis was conducted using combined SAD and MAD data. Results BRII-778 as single dose or multiple doses was generally safe and well-tolerated when administered to healthy adult subjects. There were no Grade ≥3 AEs, SAEs or AEs leading to withdrawal in BRII-778 dosing arms. PK profiles of BRII-778 were consistent with slower oral absorption with MR formulation. The increase in exposure was less than dose proportional. Mild accumulation in plasma was observed after 3 QW BRII-778-A3 doses. BRII-778-A3 750 mg under the fed state enhanced bioavailability by improving gastric dissolution and/or subsequent absorption. Exploratory C-QTc analysis confirmed a concentration-dependent effect on the QTc interval with escalating doses of BRII-778, but the interpretations are limited by small sample size. There were no clinically significant EKG changes and no individual subject met QTc stopping criteria. Conclusion SAD and MAD administration of BRII-778 formulations were generally safe and well tolerated. Rilpivirine PK profiles post BRII-778 dosing supports further evaluation of BRII-778 for potential QW regimen. Disclosures David A. Margolis, MD MPH, Brii Biosciences: Stocks/Bonds Ji Ma, PhD, Brii Biosciences: Stocks/Bonds Michael Watkins, PharmD, Brii Biosciences: Stocks/Bonds Yujin Wang, M.Sc., Brii Biosciences: Stocks/Bonds Chetana Trivedi, B.A., Brii Biosciences: Stocks/Bonds Xuelian Wei, PhD, Brii Biosciences: Stocks/Bonds Lijie Zhong, PhD, Brii Biosciences: Stocks/Bonds Kamlesh Patel, PhD, Brii Biosciences: Stocks/Bonds Li Yan, MD PhD, Brii Biosciences: Stocks/Bonds Zhi Hong, PhD, Brii Biosciences: Ownership Interest Jean-Luc Girardet, PhD, Brii Biosciences: Stocks/Bonds Lianhong Xu, PhD, Brii Biosciences: Stocks/Bonds.

Evaluation of Deutetrabenazine's Potential to Delay Cardiac Repolarization Using Concentration-QTc Analysis.

Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (α-dihydrotetrabenazine [α-HTBZ] and β-dihydrotetrabenazine [β-HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration-QTc (C-QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12-lead ECGs extracted from continuous ECG recordings. C-QTc analysis, using linear mixed-effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated α-HTBZ and β-HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C-QTc model with deuterated α-HTBZ and β-HTBZ was selected to best describe the C-QTc relationship in pooled EM and PM data. This model predicted a placebo-corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72mg doses. No subject discontinued due to cardiac-related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.

A concentration-QTc analysis of vericiguat

Abstract Introduction Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in patients with ejection fraction less than 45% who had a previous decompensation event. A dedicated, randomised, Phase Ib, QT study of vericiguat (NCT03504982) in 74 adult patients with stable coronary artery disease demonstrated no clinically significant prolongation of the time-matched, placebo-adjusted change from baseline in the Fridericia-corrected QT interval (QTcF) after vericiguat 10 mg once daily at steady state. Purpose We conducted a concentration–QTc (C-QTc) modelling analysis, on data from the QT study, to investigate the potential effect of vericiguat on QTcF and define the vericiguat plasma concentration window within which a relevant prolongation in QTcF can be excluded. Methods In the QT study, the effect of vericiguat once daily (2.5 mg titrated to 5 mg and then to 10 mg [treatments A, B, C] over 42±9 days) on the QT interval was investigated. The positive control was a single dose of moxifloxacin 400 mg (treatment D) on Day 8 or Day 50 (7 days before the first vericiguat dose or 7 days after the last vericiguat dose), depending on the treatment sequence (Figure 1). Baseline electrocardiogram assessments were performed 24 h before the start of treatment (“baseline”) and at follow-up (“back-up baseline”; Figure 1). Time-matched, baseline- and placebo-adjusted QTcF (ΔΔQTc) mean values and 90% confidence intervals (CIs) were calculated. Two analytical approaches were used to calculate ΔΔQTc. The first one (“single baseline ΔΔQTc” approach) was data-driven, where ΔΔQTc was adjusted with placebo- and either “baseline” or “back-up baseline”. The second one (“modelled baseline ΔΔQTc”) accounted for individual baseline and placebo effects, such as diurnal time course, used linear mixed effects and integrated all individual baseline and placebo data. Calculated ΔΔQTc values were then related to observed vericiguat concentrations in the C-QTc modelling step, performed with linear mixed effects implemented in R (R, the R Foundation for Statistical Computing, version 3.2.5). Results The C-QTc modelling of ΔΔQTc calculated with the “single baseline ΔΔQTc” approach indicated a positive, but non-significant, slope (Figure 2A). The “modelled baseline ΔΔQTc” approach indicated a positive and statistically significant slope (Figure 2B). In both cases, the upper limits of the 90% CI were below the threshold of clinical relevance of 10 ms within the investigated exposure range (up to 745 μg/l). Conclusion Based on the presented analysis, a clinically meaningful QT prolongation was robustly excluded within the plasma concentration range associated with the recommended target dose of vericiguat 10 mg. The C-QTc analysis supports the conclusion of the primary study statistical analysis that administration of vericiguat between 2.5 and 10 mg is not associated with a clinically meaningful QTc prolongation. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA Figure 1Figure 2

Evaluation of moxifloxacin in canine and non-human primate telemetry assays: Comparison of QTc interval prolongation by timepoint and concentration-QTc analysis.

The in vivo correct QT (QTc) assay is used by the pharmaceutical industry to characterize the potential for delayed ventricular repolarization and is a core safety assay mentioned in International Conference on Harmonization (ICH) S7B guideline. The typical telemetry study involves a dose‐response analysis of QTc intervals over time using a crossover (CO) design. This method has proven utility but does not include direct integration of pharmacokinetic (PK) data. An alternative approach has been validated and is used routinely in the clinical setting that pairs pharmacodynamic (PD) responses with PK exposure (e.g., concentration‐QTc (C‐QTc) analysis. The goal of our paper was to compare the QTc sensitivity of two experimental approaches in the conscious dog and non‐human primate (NHP) QTc assays. For timepoint analysis, a conventional design using eight animals (8 × 4 CO) to detect moxifloxacin‐induced QTc prolongation was compared to a PK/PD design in a subset (N = 4) of the same animals. The findings demonstrate that both approaches are equally sensitive in detecting threshold QTc prolongation on the order of 10 ms. Both QTc models demonstrated linearity in the QTc prolongation response to moxifloxacin dose escalation (6 to 46 ms). Further, comparison with human QTc findings with moxifloxacin showed agreement and consistent translation across the three species: C‐QTc slope values were 0.7‐ (dog) and 1.2‐ (NHP) fold of the composite human value. In conclusion, our data show that dog and NHP QTc telemetry with an integrated PK arm (C‐QTc) has the potential to supplement clinical evaluation and improve integrated QTc risk assessment.

Concentration-QTc analysis for single arm studies.

Concentration-QTc (C-QTc) modeling is being increasingly used in phase 1 studies. For studies without a placebo arm (single arm studies), the scientific whitepaper by Garnett et al. ( https://doi.org/10.1007/s10928-017-9558-5 ) states that time-matched baseline adjustments may minimize the effect of diurnal variation in QTc intervals, and categorical time effects are not needed in the model. However, how diurnal variations can be accounted for when only pre-dose baselines are available is unclear. This research investigates whether including categorical time effects in the model can adjust diurnal variation in single arm studies with pre-dose baselines, where QTc prolongation is evaluated at a concentration of interest based on ΔQTc at 24h and ΔΔQTc (a model-derived difference in ΔQTc from concentration zero). To understand the operating characteristics for the models with and without categorical time effects, simulations were conducted under various scenarios considering oncology early phase studies. When the C-QTc relationship is linear, models without categorical time effects provided biased estimates for model parameters and inflated or decreased false negative rates (FNRs) depending on the pattern of diurnal variations in QTc intervals, whereas models with categorical time effects caused no biases and controlled the FNRs. For non-linear C-QTc relationships, ΔΔQTc estimations made using the model with categorical time effects were not robust. Thus, for single arm studies where only pre-dose baselines are available, we recommend collecting QTc measurements at 24h and estimating ΔQTc at a concentration of interest at 24h using the C-QTc model with categorical time effects.

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

Early-phase studies quantifying the QTc prolongation potential for a new drug often use linear concentration-QTc (C-QTc) models, assuming no delay between plasma concentrations and QTc changes. However, that assumption is not always correct. The term "hysteresis" has been utilized to describe a time lag present between a measurable concentration and a measurable effect. To detect and quantify hysteresis and its impact on study interpretation, studies with hysteresis of 0.25-4h were simulated with different doses, half-lives, and sampling schedules in a crossover design. Hysteresis was quantified using a novel method termed exposure-normalized GRI (enGRI), a proposed modification of the Glomb-Ring Index (GRI), to account for delay and magnitude of QTc effects. With realistic sampling, the rate of false negative studies (FN) increased proportionally to the delay, even for delays shorter than 1h. Using an enGRI threshold (γ) of 2ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2ms, the specificity of enGRI was > 90% throughout the investigated scenarios. We therefore propose the incorporation of enGRI when interpreting results from C-QTc analysis with the intent of characterizing QTc effects.

Baseline selection in concentration-QTc modeling: impact on assay sensitivity

ABSTRACT The baseline selection in concentration-QTc (C-QTc) modeling is not well studied in the literature. Time-matched baseline and pre-dose baseline have been commonly used as a covariate in C-QTc modeling for parallel and crossover study, respectively. It has been showed that the C-QTc model using time-matched baseline has a low chance of showing assay sensitivity in parallel study. To better understand the impacts of baseline section in C-QTc, we examined the original and subsampled moxifloxacin and placebo data from more than 50 of TQT studies submitted to FDA with regard to assay sensitivity. Our analyses show that baseline selection (time-matched, pre-dose, average) has an impact on prediction from C-QTc modeling and the impact depends on study design (parallel, crossover). The impact to categorical table of ΔQTc is unlikely to alter the interpretation of the outlier category (ΔQTc>60) that corresponds to the regulatory concern. The results presented here can guide C-QTc study design as well as baseline selection in C-QTc modeling.

Application of Trial Simulation in the Design of a Prospective Study for Concentration-QTc Analysis in Support of a Thorough QT Study Waiver.

The concentration-QTc (C-QTc) analysis is often applied in the first-in-human (FIH) study to demonstrate the absence of a QTc effect in support of a TQT waiver. However, a C-QTc analysis without properly designed sensitivity could fail to conclude the absence of a QTc effect at high concentrations, even though the compound is QTc negative. This is because the 90% confidence interval (CI) of the model-derived ∆∆QTc grows wider with increasing concentration, and the upper-bound could cross the 10-ms threshold, even though the slope is close to 0. So far, there is no simple math formula to calculate the sensitivity/specificity of a C-QTc analysis. A PK/QTc trial simulation scheme was applied to optimize the design features of a C-QTc trial in FIH studies by evaluating the study's sensitivity over a wide concentration range, circumventing the problem of not knowing the target concentration during FIH studies. It was also used to ensure that the specificity of the trial was well-controlled. Simulation showed that the study sensitivity can be quantitatively gauged by optimizing the dose range, the number of samples per subjects or subject number, and by sampling around Tmax, and at steady-state. The specificity of the trial can also be evaluated with this approach, and it is important to combine model-derived ∆∆QTc and slope estimate in the evaluation. The trial simulation approach helps maximize the probability of success of C-QTc analyses in FIH studies intended to support a TQT waiver.

Assay sensitivity in “Hybrid thorough QT/QTc (TQT)” study

ABSTRACT A concurrent positive control should be included in a thorough QTc clinical trial to validate the study according to ICH E14 guidance. Some pharmaceutical companies have started to use “hybrid TQT” study to meet ICH E14 regulatory requirements since the release of ICH E14 Q&A (R3). The “hybrid TQT” study includes the same treatment arms (therapeutic and/or supratherapeutic dose of investigational drug, placebo, and positive control) with sample size less than traditional TQT studies, but use concentration-QTc (C-QTc) analysis as primary analysis and assay sensitivity analysis. To better understand the statistical characteristics of assay sensitivity with a commonly used positive control – Moxifloxacin - in “hybrid TQT” studies, we examined the original and subsampled moxifloxacin and placebo data from more than a hundred of TQT studies submitted to FDA. The assay sensitivity results are quite consistent between classical E14 analysis and C-QTc analysis using the original datasets. Performance of assay sensitivity in “hybrid TQT” studies using subsampled data depends on number of moxifloxacin subjects, study design (crossover design and parallel design), and C-QTc model. The results presented here can aid the design of future “hybrid TQT” studies.

Evaluation of dependent variable, time effect, covariates, and covariation structure in concentration-QTc modeling: A simulation study.

The revised ICH E14 Question and Answer (R3) document issued in December 2015 enables pharmaceutical companies to use concentration-QTc (C-QTc) modeling as the primary analysis for assessing QTc prolongation risk of new drugs. A new approach by including the time effect into the current C-QTc model is introduced. Through a simulation study, we evaluated performances of different C-QTc modeling with different dependent variables, covariates, and covariance structures. This simulation study shows that C-QTc models with ΔQTc being dependent variable without time effect inflate false negative rate and that fitting C-QTc models with different dependent variables, covariates, and covariance structures impacts the control of false negative and false positive rates. Appropriate C-QTc modeling strategies with good control of false negative rate and false positive rate are recommended.

Scientific white paper on concentration-QTc modeling.

The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.

Operational Characteristics of Linear Concentration-QT Models for Assessing QTc Interval in the Thorough QT and Phase I Clinical Studies.

Concentration-QTc (C-QTc) analysis can be used as an alternative to the standard statistical methods in clinical QT studies. Pharmacokinetic/pharmacodynamics (PK/PD) simulations were performed to assess the operating characteristics of four C-QTc models. False negatives were 2-6% for crossover and 2-9% for parallel studies, with 12 to 60 subjects per treatment for a dose with 10-ms mean effect. All C-QTc models tested gave less than +1 ms mean bias in the ΔΔQTcmax prediction. The power to exclude 10 ms was >80% across all study designs and sizes, for a dose with 3-ms mean effect. The study demonstrates that linear C-QTc models have adequate sensitivity and specificity when the simulation and data analytical models are the same. C-QTc models that incorporate time- and treatment-specific terms give the least biased ΔΔQTcmax predictions under scenarios of model-misspecifications and offer an advantage when applying to real clinical data where the underlying relationship is not known.

Delayed Effects in the Exposure-Response Analysis of Clinical QTc Trials

In clinical development, thorough QT interval/corrected QT interval (QT/QTc) studies are performed to demonstrate that new investigational drugs do not change cardiac repolarization. In addition to the analysis recommended by ICH E14, exposure-response modeling has recently gained increased scientific attention. A direct concentration–QTc relationship is usually assumed with this pharmacokinetics (PK) QT analysis. Consequently, unconsidered effect delays might lead to severe bias in estimation. Although literature and the Food and Drug Administration (FDA) recommend checking for hysteresis, little guidance is given for evaluating the presence of lagged effects. Based on simulated delay scenarios, we derive a metric that allows for the detection of relevant effect delays. With this, the necessity for refined modeling of lag times can be easily recognized.