Pridopidine Does Not Significantly Prolong the QTc Interval at the Clinically Relevant Therapeutic Dose.

INTRODUCTION: Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in development for the treatment of Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). Pridopidine's activation of S1R enhances cellular processes that are crucial for neuronal function and survival but are impaired in neurodegenerative diseases. Human brain positron emission tomography (PET) imaging studies show that at the therapeutic dose of 45 mg twice daily (bid), pridopidine selectively and robustly occupies the S1R. We conducted concentration-QTc (C-QTc) analyses to assess pridopidine's effect on the QT interval and investigated its cardiac safety profile. METHODS: C-QTc analysis was conducted using data from PRIDE-HD, a phase 2, placebo-controlled trial evaluating four pridopidine doses (45, 67.5, 90, 112.5 mg bid) or placebo over 52 weeks in HD patients. Triplicate electrocardiograms (ECGs) with simultaneous plasma drug concentrations were determined in 402 patients with HD. The effect of pridopidine on the Fridericia-corrected QT interval (QTcF) was evaluated. Cardiac-related adverse events (AEs) were analyzed from PRIDE-HD alone and from pooled safety data of three double-blind, placebo-controlled trials with pridopidine in HD (HART, MermaiHD, and PRIDE-HD). RESULTS: A concentration-dependent effect of pridopidine on the change from baseline in the Fridericia-corrected QT interval (ΔQTcF) was observed, with a slope of 0.012 ms (ms) per ng/mL (90% confidence interval (CI), 0.0109-0.0127). At the therapeutic dose of 45 mg bid, the predicted placebo-corrected ΔQTcF (ΔΔQTcF) was 6.6 ms (upper bound 90% CI, 8.0 ms), which is below the level of concern and not clinically relevant. Analysis of pooled safety data from three HD trials demonstrates that at 45 mg bid, pridopidine cardiac-related AE frequencies are similar to those with placebo. No patients reached a QTcF of 500 ms and no patients experienced torsade de pointes (TdP) at any pridopidine dose. CONCLUSIONS: At the 45 mg bid therapeutic dose, pridopidine demonstrates a favorable cardiac safety profile, with an effect on the QTc interval that is below the level of concern and not clinically relevant. TRIAL REGISTRATION: PRIDE-HD (TV7820-CNS-20002) trial registration: ClinicalTrials.gov identifier, NCT02006472, EudraCT 2013-001888-23; HART (ACR16C009) trial registration: ClinicalTrials.gov identifier, NCT00724048; MermaiHD (ACR16C008) trial registration: ClinicalTrials.gov identifier, NCT00665223, EudraCT No. 2007-004988-22.

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. Case 1 illustrates a clearly negative C-QTc evaluation, despite observations of QTc prolongation at high concentrations in nonclinical studies. In case 2 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. Case 3 illustrates a positive clinical C-QTc relationship, despite negative nonclinical assays. Case 4 demonstrates a strategy for characterizing the C-QTc relationship for a nonracemic therapy and formulation optimization, and case 5 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.

Concentration-QT modelling of the novel DHFR inhibitor P218 in healthy male volunteers.

AIMS: Given the increasing emergence of drug resistance in Plasmodium, new antimalarials are urgently required. P218 is an aminopyridine that inhibits dihydrofolate reductase being developed as a malaria chemoprotective drug. Assessing the effect of new compounds on cardiac intervals is key during early drug development to determine their cardiac safety. METHODS: This double-blind, randomized, placebo-controlled, parallel group study evaluated the effect of P218 on electrocardiographic parameters following oral administration of seven single-ascending doses up to 1000 mg in 56 healthy volunteers. Participants were randomized to treatment or placebo at a 3:1 ratio. P218 was administered in the fasted state with standardized lunch served 4 hours after dosing. 12-lead ECGs were recorded in triplicate at regular intervals on the test day, and at 48, 72, 120, 168, 192 and 240 hours thereafter. Blood samples for pharmacokinetic evaluations were collected at similar time points. Concentration-effect modelling was used to assess the effect of P218 and its metabolites on cardiac intervals. RESULTS: Concentration-effect analysis showed that P218 does not prolong the QTcF, J-Tpeak or TpTe interval at all doses tested. No significant changes in QRS or PR intervals were observed. Two-sided 90% confidence intervals of subinterval effects of P218 and its metabolites were consistently below the regulatory concern threshold for all doses. Study sensitivity was confirmed by significant shortening of QTcF after a meal. CONCLUSION: Oral administration of P218 up to 1000 mg does not prolong QTcF and does not significantly change QRS or PR intervals, suggesting low risk for drug-induced proarrhythmia.

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, 14.7 milliseconds at therapeutic concentrations and 25.6 milliseconds 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.

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

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.

Confirmation of the cardiac safety of nolasiban in a randomised cohort of healthy female volunteers.

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean Cmax for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.

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 0.25-4 h 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 1 h. Using an enGRI threshold (γ) of 2 ms resulted in FN with undetected delay and FN without hysteresis at approximately the same rate. For γ = 2 ms, 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.

Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.

Effects of the Fluoroquinolones Moxifloxacin and Levofloxacin on the QT Subintervals: Sex Differences in Ventricular Repolarization.

Women are associated with longer electrocardiographic QT intervals and increased proarrhythmic risks of QT-prolonging drugs. The purpose of this study was to characterize the differences in cardiac electrophysiology between moxifloxacin and levofloxacin in men and women and to assess the balance of inward and outward currents through the analysis of QT subintervals. Data from 2 TQT studies were used to investigate the impact of moxifloxacin (400 mg) and levofloxacin (1000 and 1500 mg) on QT subintervals using algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Concentration-effect analyses were performed to establish potential relationships between the ECG effects and the concentrations of the 2 fluoroquinolones. Moxifloxacin was shown to be a more potent prolonger of QT interval corrected by Fredericia (QTcF) and had a pronounced effect on J-Tpeak c. Levofloxacin had little effect on J-Tpeak c. For moxifloxacin, the concentration-effect modeling showed a greater effect for women on QTcF and J-Tpeak c, whereas for levofloxacin the inverse was true: women had smaller QTcF and J-Tpeak c effects. The different patterns in repolarization after administration of both drugs suggested a sex difference, which may be related to the combined IKs and IKr inhibitory properties of moxifloxacin versus IKr suppression only of levofloxacin. The equipotent inhibition of IKs and IKr appears to affect women more than men. Sex hormones are known to influence cardiac ion channel expression and differences in QT duration. Differences in IKr and IKs balances, influenced by sex hormones, may explain the results. These results support the impact of sex differences on the cardiac safety assessment of drugs.

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.

Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a thorough QTc study across eleven drug candidate programs, and demonstrate that the conclusions are largely the same. The early Phase I analysis is based upon a linear mixed effect model with known covariance structure (Dosne et al. in Stat Med 36(24):3844-3857, 2017). The treatment effect was evaluated at the supratherapeutic Cmax as observed in the thorough QTc study using a non-parametric bootstrap analysis to generate 90% confidence intervals for the treatment effect, and implementation of the standardized methodology in R and SAS software yielded consistent results. The risk assessment based on the concentration-response analysis on the early Phase I data was concordant with that based on the standard analysis of the thorough QTc study for nine out of the eleven drug candidates. This retrospective analysis is consistent with and supportive of the conclusion of a previous prospective analysis by Darpo et al. (Clin Pharmacol Ther 97(4):326-335, 2015) to evaluate whether C-QTc analysis can detect QTc effects in a small study with healthy subjects.

Effect of lofexidine on cardiac repolarization during treatment of opioid withdrawal.

BACKGROUND: Lofexidine is a non-opioid treatment for opioid withdrawal syndrome. Its sympatholytic actions counteract the nor-adrenergic hyperactivity that occurs during abrupt opioid withdrawal. METHODS: The effect of lofexidine 2.16 and 2.88 mg/day on QTcF (QT interval, heart-rate corrected, Fridericia formula) was studied as part of a large, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT01863186). ECGs were time-matched to blood sampling for lofexidine concentration and were collected at prespecified timepoints over a 7-day inpatient period. Analyses included mean change-from-baseline QTcF and exposure-response modeling to predict QTcF at relevant lofexidine concentrations. RESULTS: A total of 681 adult men and women received at least 1 dose of study drug; 566 qualified for inclusion in the concentration-QTcF analysis. Most subjects were withdrawing from heroin. During the first 24 h (Days 1-2) post-baseline, small increases in QTcF were observed in all groups: 4.7 ms for lofexidine 2.16 mg, 7.4 ms for lofexidine 2.88 mg and 1.4 ms for placebo. These increases were transient; by Day 4, when lofexidine levels had reached steady-state, QTcF increases were not present. By Day 7, QTcF was decreased from baseline in all groups. Exposure-response modeling predicted <10 ms increases in QTcF at lofexidine concentrations 3 times those obtained at maximal recommended dose. CONCLUSIONS: Lofexidine was associated with small, transient QTcF increases. Decreases in QTcF that occurred with higher lofexidine concentrations argue for an indirect QTcF effect, potentially from changes in autonomic tone. Both opioid withdrawal and lofexidine's sympatholytic actions would be expected to alter sympathetic outflow over the 7-day withdrawal.

The Cardiovascular Effects of a Meal: J-Tpeak and Tpeak -Tend Assessment and Further Insights Into the Physiological Effects.

Meal intake leads to a significant and prolonged increase in cardiac output to supply the splanchnic vasculature. A meal is associated with sympathetic activation of the cardiovascular system, and food ingestion is correlated with an increase in heart rate, an increase in cardiac stroke volume, and QTc interval shortening for up to 7 hours. Given the complexity of the system, one or several of many mechanisms could explain this observation. The shortening of the QTc interval was correlated with a rise of C-peptide following food ingestion, but the mechanisms by which C-peptide may be involved in the modulation of cardiac repolarization are still unknown. This shortening of the myocardial action potential caused by the ingestion of food was further investigated in the present study by measuring the QRS, J-Tpeak , and Tpeak -Tend intervals in search of further clues to better understand the underlying mechanisms. A retrospective analysis was conducted based on data collected in a formal thorough QT/QTc study in which 32 subjects received a carbohydrate-rich "continental" breakfast, moxifloxacin without food, and moxifloxacin with food. We assessed the effect of food on T-wave morphology using validated algorithms for measurement of J-Tpeak and Tpeak -Tend intervals. Our findings demonstrate that a standardized meal significantly shortened J-Tpeak for 4 hours after a meal and to a much lesser extent and shorter duration (up to 1 hour) prolonged the Tpeak -Tend and QRS intervals. This suggests that the QTc shortening occurs mainly during phase 2 of the cardiac action potential. As there was no corresponding effect on Tpeak -Tend beyond the first hour, we conclude that a meal does not interfere with the outward correcting potassium channels but possibly with Ca2+ currents. An effect on mainly Ca2+ aligns well with our understanding of physiology whereby an increase in stroke volume, as observed after a meal, is associated with changes in Ca2+ cycling in and out of the sarcoplasmic reticulum during cardiac myocyte contraction.

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration.

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects.

Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies.

PURPOSE: The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed. METHODS: In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time-matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory. RESULTS: A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study-specific QTc interval (QTcSS), at the ulixertinib Cmax, were - 0.529 ms (90% CI - 6.621, 5.562) on day 1 and - 9.202 ms (90% CI - 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI - 1.343, 2.412) and 1.16 (90% CI - 1.732, 4.042) ms per µg/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals. CONCLUSIONS: Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters. REGISTRATION: The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries.

Evaluating Potential QT Effects of JNJ-54861911, a BACE Inhibitor in Single- and Multiple-Ascending Dose Studies, and a Thorough QT Trial With Additional Retrospective Confirmation, Using Concentration-QTc Analysis.

Nonclinical assays with JNJ-54861911, a ß-secretase 1 inhibitor have indicated that at high concentrations, it may delay cardiac repolarization. A 4-way crossover thorough QT (TQT) study was performed in 64 healthy subjects with 50 and 150 mg JNJ-54861911 once daily for 7 days, placebo, and 400 mg moxifloxacin. Retrospective high-precision QT (HPQT) analysis was performed on serial elecrocardiograms extracted from first-in-human single-ascending dose (SAD) and multiple-ascending dose (MAD) studies to evaluate if early studies could detect and predict QT effect. In the TQT study, a high therapeutic 50 mg dose did not cause QT prolongation, and an effect >10 milliseconds could be excluded at all postdose timepoints. QT prolongation with peak effect on placebo-corrected change from baseline QTcF of 15.5 milliseconds (90%CI, 12.9-18.1 milliseconds) was observed following a supratherapeutic dose (150 mg). No clinically relevant QT changes were observed in earlier studies. However, with SAD/MAD findings by HPQT, the slope of the exposure-response (ER) relationship in the SAD study (doses up to 150 mg) was similar to the TQT study slope, and the estimated QT effect was comparable at high plasma levels. In the MAD study, doses up to 90 mg once daily for 7 days resulted in JNJ-54861911 peak plasma concentrations (Cmax ) comparable to those in the SAD study (∼750 ng/mL), but ER by HPQT failed to detect a QT effect and resulted in negative estimations. Adding a higher dose cohort (150 mg; Cmax , 1125 ng/mL) demonstrated a QT effect, with a slightly lower ER slope than the TQT study. JNJ-54861911 (up to 50 mg) did not cause QT prolongation at clinically relevant plasma concentrations in any studies. Provided sufficiently high plasma concentrations were captured, mild QT prolongation observed postdose with a supratherapeutic dose could be detected (TQT study) and estimated in SAD/MAD studies. Based on population pharmacokinetic modeling and simulation, 5 and 25 mg doses are currently considered for further phase 3 studies and are expected not to cause any relevant QT prolongation.

Confirmation of the Cardiac Safety of PGF2α Receptor Antagonist OBE022 in a First-in-Human Study in Healthy Subjects, Using Intensive ECG Assessments.

OBE022, a new orally active prostaglandin F2α  receptor antagonist (OBE022) with myometrial selectivity is being developed to reduce uterine contractions during preterm labor. This first-in-human study evaluated the effect of OBE022 following multiple doses on the QT interval in 23 healthy postmenopausal women, using the effect of a meal on QTc to demonstrate assay sensitivity. We report the cardiac safety outcome performed during the multiple ascending part of this trial. OBE022 was administered after a standardized breakfast on day 1 and in the fasted state from day 3 to day 9 wth a standardized lunch 4 hours after administration. Concentration-effect modeling was used to assess the effect of prodrug OBE022 and parent OBE002 on QTc after a single dose (days 1 and 3) and multiple doses (day 9). The concentration-response analysis showed the absence of QTc prolongation at all doses tested. Two-sided 90% confidence intervals of the geometric mean Cmax  for estimated QTc effects of OBE022 and OBE002 of all dose groups were consistently below the threshold of regulatory concern. The sensitivity of this study to detect small changes in the QTc was confirmed by a significant shortening of the QTc on days 1, 3, and 9 after standardized meals. This study establishes that neither prodrug OBE022 nor parent OBE002 prolong the QTc interval. The observed food effect on the QT interval validated the assay on all assessment days. Both the change from predose, premeal and the change from premeal, postdose demonstrated the specificity of the method.

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

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%.

Correction to: Scientific white paper on concentration-QTc modeling.

The original version of this article unfortunately contained an error in Equation 1 under the section "Pre-specified linear mixed effects model". The correct equation has given below.