Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Omecamtiv mecarbil does not prolong QTc intervals at therapeutic concentrations.

AIMS: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval. METHODS: In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n = 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. RESULTS: After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7 ms at 1 hour postdose to -0.8 ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7 ms (4 h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1 ms (90% CI: 11.71-14.57) at 3 hours; lower bound of the 1-sided 95% CI was > 5 ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10 ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSION: OM does not have a clinically relevant effect on the studied ECG parameters.

E2027 Cardiac Safety Evaluation With Concentration-Response Modeling of ECG Data to Inform Dose Selection in Studies in Patients With Dementia With Lewy Bodies.

BACKGROUND: E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. PATIENTS AND METHODS: A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. RESULTS: A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of ∼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. CONCLUSION: This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.

Intravenous Amisulpride Does Not Meaningfully Prolong the QTc Interval at Doses Effective for the Management of Postoperative Nausea and Vomiting.

BACKGROUND: Postoperative nausea and vomiting (PONV) are significant issues in surgical patients, and additional treatment options are needed. Dopaminergic antiemetics have been popular for their efficacy, but their use has been limited by safety concerns, especially the potential for torsade de pointes arising from QT interval prolongation. Intravenous (IV) amisulpride, a dopamine D2 and D3 antagonist shown to be effective at preventing and treating PONV at doses of 5 and 10 mg, respectively, has a dose-dependent effect on QT but at 5 mg is not associated with clinically meaningful prolongation of the heart rate-corrected QT (QTc) interval. This study was designed to evaluate the QT effect of a 10-mg dose of amisulpride, alone and when simultaneously coadministered with ondansetron, an antiemetic of a different class, also known to prolong the QT interval. METHODS: In this randomized, double-blind, placebo-controlled, 3-period, crossover study, healthy male and female volunteers 18-65 years of age received IV, in a random sequence: (1) amisulpride 10 mg given twice, 2 hours apart; (2) amisulpride 10 mg and ondansetron 4 mg, given simultaneously; and (3) placebo. RESULTS: Thirty subjects were enrolled, and 29 completed all 3 treatment periods. The largest mean placebo-corrected change-from-baseline QT interval corrected for heart rate using Fridericia's formula (QTcF) (ΔΔQTcF) after the first and second amisulpride dose was 5.2 milliseconds (90% confidence interval [CI], 3.53-6.96 milliseconds) and 8.0 milliseconds (90% CI, 5.49-10.58 milliseconds), respectively. After coadministration of amisulpride and ondansetron, the largest mean ΔΔQTcF was 7.3 milliseconds (90% CI, 5.48-9.16 milliseconds). The slope of the amisulpride concentration-change-from-baseline QTcF (ΔQTcF) relationship was 0.006 ms/ng/mL (90% CI, 0.0020-0.0098). No QTc outliers (absolute QTcF value >480 milliseconds or increase from baseline >30 milliseconds) were seen in any period. CONCLUSIONS: A 10-mg dose of IV amisulpride, given alone or in combination with ondansetron, does not have a clinically significant effect on the QT interval.

Randomized, Double-Blind, Placebo- and Positive-Controlled Crossover Study of the Effects of Omadacycline on QT/QTc Intervals in Healthy Subjects.

Omadacycline, an aminomethylcycline, is an antibiotic that is approved in the United States for once-daily intravenous (i.v.) and oral use for treatment of adults with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. In this thorough QT study, the effects of a therapeutic (100 mg i.v.) dose and a supratherapeutic (300 mg i.v.) dose of omadacycline on the electrocardiogram were studied, with placebo and moxifloxacin as negative and positive controls. Omadacycline at these doses had no effect on the QTc interval. The largest mean placebo-corrected change-from-baseline QTcS (ΔQTcS) were 1.7 ms (90% confidence interval [CI], 0.06 to 3.30) and 2.6 ms (90% CI, 0.55 to 4.67), observed at 20 min and 2 h after the start of the infusion of 100 mg and 300 mg, respectively. Assay sensitivity was demonstrated with moxifloxacin, which caused clear prolongation of QTcS, with the largest mean placebo-corrected ΔQTcS of 9.8 ms at 1.5 and 2 h. With a linear exposure-response model, the estimated slope of the concentration-change-from-baseline QTcF (ΔQTcF) relationship was very shallow: 0.0007 ms per ng/ml (90% CI, 0.0000 to 0.0014). The possibility of an effect on placebo-corrected ΔQTcS exceeding 10 ms can be excluded at omadacycline concentrations in plasma of up to ∼8 µg/ml. Omadacycline had no effect on cardiac conduction (PR and QRS intervals) but caused an increase in heart rate of 16.8 beats per min at 35 min after the 100-mg dose and 21.6 beats per min at 50 min after the 300-mg dose.

Estimation of age effect with change-points on survival of cancer patients.

There is a global trend that the average onset age of many human complex diseases is decreasing, and the age of cancer patients becomes more spread out. The age effect on survival is nonlinear in practice and may have one or more important change-points at which the trend of the effect can be very different before and after these threshold ages. Identification of these change-points allows clinical researchers to understand the biologic basis for the complex relation between age and prognosis for optimal prognostic decision. This paper considers estimation of the potentially nonlinear age effect for general partly linear survival models to ensure a valid statistical inference on the treatment effect. A simple and efficient sieve maximum likelihood estimation method that can be implemented easily using standard statistical software is proposed. A data-driven adaptive algorithm to determine the optimal location and the number of knots for the identification of the change-points is suggested. Simulation studies are performed to study the performance of the proposed method. For illustration purpose, the method is applied to a breast cancer data set from the public domain to investigate the effect of onset age on the disease-free survival of the patients. The results revealed that the risk is highest among young patients and young postmenopausal patients, probably because of a change in hormonal environment during a certain phase of menopause.

Independence screening for high dimensional nonlinear additive ODE models with applications to dynamic gene regulatory networks.

Mechanism-driven low-dimensional ordinary differential equation (ODE) models are often used to model viral dynamics at cellular levels and epidemics of infectious diseases. However, low-dimensional mechanism-based ODE models are limited for modeling infectious diseases at molecular levels such as transcriptomic or proteomic levels, which is critical to understand pathogenesis of diseases. Although linear ODE models have been proposed for gene regulatory networks (GRNs), nonlinear regulations are common in GRNs. The reconstruction of large-scale nonlinear networks from time-course gene expression data remains an unresolved issue. Here, we use high-dimensional nonlinear additive ODEs to model GRNs and propose a 4-step procedure to efficiently perform variable selection for nonlinear ODEs. To tackle the challenge of high dimensionality, we couple the 2-stage smoothing-based estimation method for ODEs and a nonlinear independence screening method to perform variable selection for the nonlinear ODE models. We have shown that our method possesses the sure screening property and it can handle problems with non-polynomial dimensionality. Numerical performance of the proposed method is illustrated with simulated data and a real data example for identifying the dynamic GRN of Saccharomyces cerevisiae.

Variable Selection for Sparse High-Dimensional Nonlinear Regression Models by Combining Nonnegative Garrote and Sure Independence Screening.

In many regression problems, the relations between the covariates and the response may be nonlinear. Motivated by the application of reconstructing a gene regulatory network, we consider a sparse high-dimensional additive model with the additive components being some known nonlinear functions with unknown parameters. To identify the subset of important covariates, we propose a new method for simultaneous variable selection and parameter estimation by iteratively combining a large-scale variable screening (the nonlinear independence screening, NLIS) and a moderate-scale model selection (the nonnegative garrote, NNG) for the nonlinear additive regressions. We have shown that the NLIS procedure possesses the sure screening property and it is able to handle problems with non-polynomial dimensionality; and for finite dimension problems, the NNG for the nonlinear additive regressions has selection consistency for the unimportant covariates and also estimation consistency for the parameter estimates of the important covariates. The proposed method is applied to simulated data and a real data example for identifying gene regulations to illustrate its numerical performance.

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.

Concentration-QTcF Modeling of Icenticaftor from a Randomized, Placebo- and Positive-Controlled Thorough QT Study in Healthy Participants.

Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor. Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with chronic obstructive pulmonary disease by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade. A placebo- and positive-controlled, 4-way crossover thorough QT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supratherapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on electrocardiogram parameters, including concentration-corrected QT (QTc) analysis. Moxifloxacin (400 mg, oral) was used as a positive control. In the concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL. The effect on the Fridericia corrected QT (QTcF) interval (∆ΔQTcF) was predicted to be -1.3 milliseconds at the icenticaftor 300-mg twice-daily peak concentration (geometric mean was 1094 ng/mL) and -5.5 milliseconds at the 750-mg twice-daily peak concentration (geometric mean Cmax was 4529 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by-time-point analysis indicated least squares placebo corrected mean ∆∆QTcF across time points ranged from -7.9 to 0.1 milliseconds at 1 and 24 hours after dosing both on Day 6 in the 750-mg dose group compared with -3.7 to 1.6 milliseconds at 1.5 and 24 hours after dosing on Day 1 in the 300-mg dose group. Assay sensitivity was demonstrated with moxifloxacin. The large accumulation of exposures, especially the 4.3-fold increase in peak plasma concentration observed at the icenticaftor 750-mg twice-daily dosage compared with Icenticaftor 300 mg twice daily (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of icenticaftor on ΔΔQTcF. Based on the concentration-QTc analysis, an effect on ΔΔQTcF exceeding 10 milliseconds can be excluded within the full observed ranges of plasma concentrations on icenticaftor, up to approximately 9540 ng/mL. Icenticaftor at the studied doses demonstrated a mild shortening in QTcF, which is unlikely to be of clinical relevance in a therapeutic setting.

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 ß-dihydrotetrabenazine [ß-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 72 mg) 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 ß-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 ß-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 72 mg 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 randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia.

This study (NCT04369391) evaluated the effects of ulotaront (SEP-363856), a novel trace amine-associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single-dose, three-period crossover (ulotaront 150 mg, placebo, moxifloxacin 400 mg). Sixty subjects with schizophrenia completed all periods. Ulotaront had no clinically relevant effect on heart rate, PR interval, or QRS duration. In by-time-point analysis (secondary analysis), the upper bound of the two-sided 90% confidence interval for ΔΔQTcF (QT interval corrected for heart rate using Fridericia's formula) was below 10 ms at all time points for ulotaront. In concentration-QTc analysis (primary analysis), a linear mixed-effects model with ulotaront and its major metabolite SEP-383103 was selected as the primary model based on prespecified criteria. Effect on ∆∆QTcF exceeding 10 ms can be excluded within observed ranges of ulotaront and SEP-383103 plasma concentrations up to ~574 and ~272 ng/mL, respectively. The upper bound of 90% CI for ΔΔQTcF can be predicted to be below 10 ms at the highest anticipated clinical exposure, currently defined as steady-state mean Cmax at ulotaront 100 mg/day in CYP2D6 poor metabolizers, ~416 and ~211 ng/mL for ulotaront and SEP-383103, respectively. Assay sensitivity was demonstrated by the QTc effect caused by moxifloxacin. In conclusion, ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia at the anticipated maximum therapeutic dose.

Concentration-QTc Relationship from a Single Ascending Dose Study of ANAVEX3-71, a Novel Sigma-1 Receptor and Allosteric M1 Muscarinic Receptor Agonist in Development for the Treatment of Frontotemporal Dementia, Schizophrenia, and Alzheimer's Disease.

This is the cardiodynamic evaluation of a single ascending dose study in healthy participants with the primary objective of assessing the effect of ANAVEX3-71, formerly AF710B, on ECG parameters. Twelve-lead ECGs were obtained at 3 time points within 1 hour prior to dosing to establish a baseline and then serially postdose. Concentration-QTc analysis of plasma concentrations of ANAVEX3-71 and metabolite M8 was conducted. ANAVEX3-71 at the studied doses did not have a clinically relevant effect on heart rate or on the PR and QRS intervals. ANAVEX3-71 alone was retained in the primary model due to small fit differences between models which included the metabolite M8. The estimated population slope of the concentration-QTcF relationship was small and slightly negative: -0.017 ms per µg/L, with a small treatment effect-specific intercept of -0.49 ms. An effect on the placebo-corrected, change-from-baseline QTc exceeding 10 ms can be excluded within the full observed ranges of plasma concentrations of ANAVEX3-71 and M8 up to ∼996 and ∼58 µg/L, respectively. The results from this cardiodynamic evaluation demonstrated that ANAVEX3-71 at single ascending doses of 5-200 mg had no clinically relevant effects on any of the studied ECG parameters.

Numerical discretization-based estimation methods for ordinary differential equation models via penalized spline smoothing with applications in biomedical research.

Differential equations are extensively used for modeling dynamics of physical processes in many scientific fields such as engineering, physics, and biomedical sciences. Parameter estimation of differential equation models is a challenging problem because of high computational cost and high-dimensional parameter space. In this article, we propose a novel class of methods for estimating parameters in ordinary differential equation (ODE) models, which is motivated by HIV dynamics modeling. The new methods exploit the form of numerical discretization algorithms for an ODE solver to formulate estimating equations. First, a penalized-spline approach is employed to estimate the state variables and the estimated state variables are then plugged in a discretization formula of an ODE solver to obtain the ODE parameter estimates via a regression approach. We consider three different order of discretization methods, Euler's method, trapezoidal rule, and Runge-Kutta method. A higher-order numerical algorithm reduces numerical error in the approximation of the derivative, which produces a more accurate estimate, but its computational cost is higher. To balance the computational cost and estimation accuracy, we demonstrate, via simulation studies, that the trapezoidal discretization-based estimate is the best and is recommended for practical use. The asymptotic properties for the proposed numerical discretization-based estimators are established. Comparisons between the proposed methods and existing methods show a clear benefit of the proposed methods in regards to the trade-off between computational cost and estimation accuracy. We apply the proposed methods t an HIV study to further illustrate the usefulness of the proposed approaches.

A Phase 1 Clinical Study Evaluating the Effects of Cenobamate on the QT Interval.

Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1-63) up-titrated by 50-mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo-moxifloxacin (days -1 and 64); (B) moxifloxacin 400 mg (day -1; positive control), placebo-cenobamate (days 1-63), and placebo-moxifloxacin (day 64); and (C) placebo-moxifloxacin (day -1), placebo-cenobamate (days 1-64), and moxifloxacin 400 mg (day 64). The primary end point was baseline-adjusted, placebo-corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, -10.8 milliseconds; day 63, -18.4 milliseconds). Based on concentration-QTc analysis, ∆∆QTcF effect was predicted as -9.85 and -17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 µg/mL) and supratherapeutic (500 mg/day; 63.96 µg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose-related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc-prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short-QT syndrome and caution should be used when coadministering with drugs that shorten QT interval.

A Phase 1 Thorough QT/QTc Study of Therapeutic and Supratherapeutic Doses of Belumosudil in Healthy Subjects.

Belumosudil is a selective Rho-associated, coiled-coil-containing protein kinase-2 inhibitor. In this crossover design thorough QT/QTc study, single therapeutic (200 mg) and supratherapeutic (1000 mg) oral doses of belumosudil, moxifloxacin (positive control), and placebo were administered to 34 subjects. Twelve-lead electrocardiograms and serial pharmacokinetic sampling were acquired. The effect of belumosudil on the placebo-corrected, change-from-baseline QTcF was small, and an effect exceeding 10 ms could be excluded across all time points with both doses. Using concentration-QTc analysis, an effect on ΔΔQTcF >10 ms can be excluded up to belumosudil concentrations of ≈12 080 ng/mL, more than 2-fold above mean Cmax after the supratherapeutic dose. There was no clinically relevant effect on heart rate or cardiac conduction (ie, the PR and QRS intervals) for belumosudil. No differences in safety were noted between belumosudil and placebo treatment. Assay sensitivity was demonstrated by moxifloxacin's effect on the QTc interval. In conclusion, belumosudil at therapeutic and supratherapeutic doses did not have a clinically meaningful effect on electrocardiogram parameters.

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.

A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects.

This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two-part phase I study (anzctr.org.au ACTRN12618001036202). Part A was a randomized, open-label, three-period, single-dose crossover study (n = 12) with rilzabrutinib 100 mg ± ritonavir 100 mg or rilzabrutinib 1200 mg. Part B was a randomized, double-blind, placebo-controlled, four-way, single-dose crossover study (n = 39) with matched placebo, rilzabrutinib 400 mg ± ritonavir 100 mg, or moxifloxacin (positive control). Primary objectives: part A - pharmacokinetics (PK) of rilzabrutinib ± ritonavir, safety, and optimal dose for Part B; Part B - effect of rilzabrutinib therapeutic and supratherapeutic concentration on electrocardiogram (ECG) parameters. ECGs and PK samples were serially recorded before and post-dose. In part A, rilzabrutinib 100 mg + ritonavir led to 17-fold area under the concentration-time curve (AUC0-∞ ) and 7-fold maximum plasma concentration (Cmax ) increases over rilzabrutinib alone. Rilzabrutinib 1200 mg was discontinued due to mild-to-moderate gastrointestinal intolerance. In Part B, rilzabrutinib 400 mg + ritonavir increased rilzabrutinib mean AUC0-∞ from 454 to 3800 ng h/mL and Cmax from 144 to 712 ng/mL. The concentration-QTc relationship was slightly negative, shallow (-0.01 ms/ng/mL [90% CI -0.016 to -0.001]), and an effect >10 ms on QTcF could be excluded within the observed range of plasma concentrations, up to 2500 ng/mL. Safety was similar to other studies of rilzabrutinib. In conclusion, rilzabrutinib, even at supratherapeutic doses, had no clinically relevant effects on ECG parameters, including the QTc interval.

Safety, Pharmacokinetics, and Pharmacodynamics of Trazpiroben (TAK-906), a Novel Selective D2 /D3 Receptor Antagonist: A Phase 1 Randomized, Placebo-Controlled Single- and Multiple-Dose Escalation Study in Healthy Participants.

Gastroparesis is a chronic neuromuscular disorder of the upper gastrointestinal tract in which episodic exacerbation can lead to frequent hospitalizations and severe disability. Dopamine D2 /D3 receptor antagonists have been used to treat patients with gastroparesis with some efficacy; however, their chronic use is limited owing to associated central nervous system (CNS) or cardiovascular safety concerns. Trazpiroben (TAK-906) is a dopamine D2 /D3 receptor antagonist under development for the long-term treatment of gastroparesis. Preclinical studies in rat and dog have shown trazpiroben to have minimal brain penetration and low affinity for the human ether-à-go-go-related gene (hERG) potassium channel (IC50 ,  15.6 µM), thereby reducing the risk of the CNS and cardiovascular adverse effects seen with other dopamine D2 /D3 receptor antagonists. This phase 1 trial evaluated the safety, pharmacokinetics, and pharmacodynamics of trazpiroben in healthy participants. Trazpiroben was rapidly absorbed and eliminated (Tmax , ∼1.1 hours; t1/2 , 4-11 hours) after administration of single (5-300 mg) and multiple (50 or 100 mg) doses. Receptor target engagement was confirmed for all doses, as indicated by an increase in serum prolactin levels compared with placebo (mean prolactin Cmax , 134.3 ng/mL after administration of trazpiroben 10 mg vs 16.1 ng/mL with placebo). Therapeutically relevant single and multiple doses of trazpiroben were well tolerated in healthy participants, and no clinically meaningful cardiovascular adverse effects were observed across the whole dose range. These data support the further development of trazpiroben for the treatment of gastroparesis.

Evaluation of the Potential for QTc Prolongation With Repeated Oral Doses of Fedratinib in Patients With Advanced Solid Tumors.

The impact of repeated daily 500-mg fedratinib (an oral selective Janus kinase [JAK] 2 inhibitor) on QTc and other electrocardiogram (ECG) parameters was assessed in 60 patients with advanced solid tumors. Patients received placebo on day 1 and fedratinib 500 mg daily for 14 days. Concentration-QTc analysis was performed with change-from-baseline QTc corrected by Fridericia's formula (ΔQTcF) as the dependent variable. Fedratinib median time to maximum plasma concentration (Cmax ) was observed 3 hours postdose on day 15. The largest difference between means for fedratinib and placebo was 0.5 bpm (90%CI, -2.75 to 3.72 bpm) for heart rate (3 hours postdose) and 4.3 milliseconds (90%CI, 1.04-7.60 milliseconds) for QTcF (4 hours postdose). The estimated slope of the fedratinib concentration-QTcF relationship was shallow and not statistically significant: -0.0005 milliseconds per ng/mL (90%CI, -0.00145 to 0.00050 milliseconds per ng/mL). Predicted fedratinib placebo-corrected ΔQTcF was 0.6 milliseconds (90%CI, -1.80 to 2.93 milliseconds) at the geometric mean of the observed Cmax (3615 ng/mL). Fedratinib did not affect PR or QRS intervals. No patients had QTcF > 60 milliseconds, and no patients experienced QTcF ≥ 500 milliseconds. Fedratinib did not cause clinically relevant ECG effects or QTc prolongation. Safety findings were consistent with the known safety profile.