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.

Diurnal QT analysis in patients with sotalol after cardioversion of atrial fibrillation.

BACKGROUND: The risk of ventricular arrhythmias in patients on QT prolonging drugs is indicated to be increased early after cardioversion (CV) of atrial fibrillation (AF) to sinus rhythm (SR). Sotalol, used to prevent AF relapse, prolongs cardiac repolarization and corrected QT interval (QTc). A pronounced QTc prolongation is an established marker of pro-arrhythmias. Our objective was to use novel technique to quantify and evaluate the diurnal variation of the QTc interval after elective CV to SR in patients on sotalol or metoprolol. METHODS: Fifty patients underwent twelve-lead Holter recording for 24 hr after elective CV for persistent AF. All patients had the highest tolerable stable dose of sotalol (n = 27) or metoprolol (n = 23). Measurements of QT and RR intervals were performed on all valid beats. RESULTS: A clear diurnal variation of both HR and QTc was seen in both groups, more pronounced in patients on sotalol, where a high percentage of heartbeats with QTc >500 ms was observed, especially at night. Six patients (22%) on sotalol but none on metoprolol had >20% of all heart beats within the 24-hour recording with QTc >500 ms. CONCLUSION: Twenty-four-hour Holter recordings with QT-measurement immediately after CV demonstrated that one in five patients on sotalol had >20% of all heart beats with prolonged QTc >500 ms, especially during night-time. The QTc diurnal variation was retained in patients on ß-blockade or a potent class III anti-arrhythmic drug with ß-blocking properties.

Comparison of electrocardiograms (ECG) waveforms and centralized ECG measurements between a simple 6-lead mobile ECG device and a standard 12-lead ECG.

BACKGROUND: Interval duration measurements (IDMs) were compared between standard 12-lead electrocardiograms (ECGs) and 6-lead ECGs recorded with AliveCor's KardiaMobile 6L, a hand-held mobile device designed for use by patients at home. METHODS: Electrocardiograms were recorded within, on average, 15 min from 705 patients in Mayo Clinic's Windland Smith Rice Genetic Heart Rhythm Clinic. Interpretable 12-lead and 6-lead recordings were available for 685 out of 705 (97%) eligible patients. The most common diagnosis was congenital long QT syndrome (LQTS, 343/685 [50%]), followed by unaffected relatives and patients (146/685 [21%]), and patients with other genetic heart diseases, including hypertrophic cardiomyopathy (36 [5.2%]), arrhythmogenic cardiomyopathy (23 [3.4%]), and idiopathic ventricular fibrillation (14 [2.0%]). IDMs were performed by a central ECG laboratory using lead II with a semi-automated technique. RESULTS: Despite differences in patient position (supine for 12-lead ECGs and sitting for 6-lead ECGs), mean IDMs were comparable, with mean values for the 12-lead and 6-lead ECGs for QTcF, heart rate, PR, and QRS differing by 2.6 ms, -5.5 beats per minute, 1.0 and 1.2 ms, respectively. Despite a modest difference in heart rate, intervals were close enough to allow a detection of clinically meaningful abnormalities. CONCLUSIONS: The 6-lead hand-held device is potentially useful for a clinical follow-up of remote patients, and for a safety follow-up of patients participating in clinical trials who cannot visit the investigational site. This technology may extend the use of 12-lead ECG recordings during the current COVID-19 pandemic as remote patient monitoring becomes more common in virtual or hybrid-design clinical studies.

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.

Potential strategy for assessing QT/QTc interval for drugs that produce rapid changes in heart rate: Electrocardiographic assessment of the effects of intravenous remimazolam on cardiac repolarization.

AIMS: Remimazolam is a new, ultra-short-acting benzodiazepine developed for intravenous (IV) use during procedural sedation and in general anaesthesia. Two trials were conducted to characterize its effects on cardiac repolarization. METHODS: A thorough QT/QTc (TQT) study assessed electrocardiography effects of therapeutic and supratherapeutic doses of remimazolam and midazolam. To investigate whether RR-QT hysteresis effects due to rapid heart rate changes might have confounded the QTc assessments in the TQT trial, a second trial used continuous IV remimazolam infusion to achieve stable heart rates during periods of stable remimazolam plasma concentration. RESULTS: During the TQT, both compounds produced a 10-20-beats/min increase in heart rate within 30 seconds, persisting for 5-10 minutes. Within 30 seconds, the upper bound of the 2-sided 90% confidence interval for the placebo-corrected change from baseline for QTcI (ΔΔQTcI) exceeded 10 ms for both doses of remimazolam (ΔΔQTcI 7.2 [3.2, 11.2] ms for the 10 mg dose and 10.4 [6.5, 14.3] ms for the 20 mg dose) as well as for the 7.5-mg dose of midazolam (8.2 [4.4, 12.1] ms). At 2 minutes after IV bolus, the upper bound of the 2-sided 90% confidence interval for ΔΔQTcI exceeded 10 ms only for the remimazolam 20-mg dose (6.3 [2.3, 10.2] ms). During the second study, during periods of stable heart rate, remimazolam had no clinically significant effect on QTc (peak ΔΔQTcI 3.4 [-1.1, 7.6] ms). CONCLUSION: Remimazolam does not prolong cardiac repolarization (QTc). The methods reported here may allow assessment of the QTc effects of other drugs given by IV bolus.

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.

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.

Effects of intranasal kinetic oscillation stimulation on heart rate variability.

BACKGROUND: Kinetic oscillation stimulation in the nasal cavity (KOS) has been shown to have positive symptomatic effects in subjects with non-allergic rhinitis and in patients with migraine. METHODS: To evaluate the effect of KOS on autonomic function, we assessed heart rate variability (HRV) in this small exploratory study in 12 healthy subjects. KOS treatment was performed using a minimally invasive system with a single-use catheter inserted into the nasal cavity. During treatment, the tip was inflated and oscillated with a mean pressure of 95 millibar and amplitude of the oscillations of 100 millibar at a frequency of 68 Hz. Treatment was given for 15 minutes sequentially on each side. Heart rate variability was assessed during five 30-minutes periods before, during and immediately after KOS treatment and 3.5 hours thereafter. KOS resulted in a substantial reduction of HRV. RESULTS: As compared to baseline recorded during 30 minutes preceding treatment, VLF was reduced by 65%, LF by 55%, the ratio LF/HF by 44%, with somewhat smaller observed effects in the time domain; SDNN and RMSDD were reduced by of 36% and 18%, respectively. Heart rate remained stable during treatment with minimal mean changes from 68 ± 7 bpm before to 68 ± 9 and 69 ± 9 bpm during and after treatment. Reduction of HRV parameters was consistently seen in all subjects, with rapid onset and return towards baseline values during post-treatment observation periods. CONCLUSIONS: KOS has an effect on the autonomic balance with pronounced heart-rate independent reduction on HRV.

A Phase I, Randomized, Double-Blinded, Placebo- and Moxifloxacin-Controlled, Four-Period Crossover Study To Evaluate the Effect of Gepotidacin on Cardiac Conduction as Assessed by 12-Lead Electrocardiogram in Healthy Volunteers.

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic in development for treatment of conventional and biothreat infections. This was a single-dose, crossover thorough QT study in healthy subjects who were administered intravenous (i.v.) gepotidacin as a therapeutic (1,000-mg) dose and supratherapeutic (1,800-mg) dose, placebo, and 400 mg oral moxifloxacin in 4 separate treatment periods. Gepotidacin caused a mild effect on heart rate, with a largest placebo-corrected change-from-baseline heart rate of 7 and 10 beats per minute at the end of the 1,000-mg and 1,800-mg infusion, respectively. Gepotidacin caused an increase of change-from-baseline QTcF (ΔQTcF), with a peak effect at the end of infusion. The largest mean placebo-corrected ΔQTcF (ΔΔQTcF) was 12.1 ms (90% confidence interval [CI], 9.5 to 14.8) and 22.2 ms (90% CI, 19.6 to 24.9) after 1,000 mg and 1,800 mg, respectively. ΔΔQTcF rapidly fell after the end of the infusion, with a mean ΔΔQTcF of 6.1 ms 60 min after the 1,800-mg dose. Exposure-response analysis demonstrated a statistically significant positive relationship between gepotidacin plasma levels and ΔΔQTcF, with a slope of 1.45 ms per µg/ml (90% CI, 1.30 to 1.61). Using this model, the effect on ΔΔQTcF can be predicted to be 11 and 20 ms at the observed mean peak plasma concentration after the infusion of gepotidacin at 1,000 mg (7 µg/ml) and 1,800 mg (13 µg/ml), respectively. In conclusion, gepotidacin caused QT prolongation in this thorough QT study, and a mean effect can be predicted to less than 15 ms at the highest expected plasma concentration, 9 µg/ml. (This study has been registered at ClinicalTrials.gov under identifier NCT02257398.).

Solithromycin, a novel macrolide, does not prolong cardiac repolarization: a randomized, three-way crossover study in healthy subjects.

BACKGROUND: Macrolide antibiotics may cause QT prolongation. OBJECTIVES: To study the QT effect of a novel macrolide, solithromycin. METHODS: This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h. RESULTS: After the 40 min infusion of 800 mg of solithromycin, the geometric mean solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) µg/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (ΔQTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) for solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; P = 0.0001) was observed with solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval. CONCLUSIONS: The study demonstrated that solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation.

Comparing QT interval variability of semiautomated and high-precision ECG methodologies in seven thorough QT studies-implications for the power of studies intended for definitive evaluation of a drug's QT effect.

BACKGROUND: In studies of drug effects on electrocardiographic parameters, the level of precision in measuring QTc interval changes will influence a study's ability to detect small effects. METHODS: Variability data from investigational, placebo and moxifloxacin treatments from seven thorough QT studies performed by the same sponsor were analyzed with the objective to compare the performance of two commonly used approaches for ECG interval measurements: semiautomated (SA) and the high-precision QT (HPQT) analysis. Five studies were crossover and two parallel. Harmonized procedures were implemented to ensure similar experimental conditions across studies. ECG replicates were extracted serially from continuous 12-lead recordings at predefined time points from subjects supinely resting. The variability estimates were based on the time-point analysis of change-from-baseline QTcF as the dependent variable for the standard primary analysis of previous thorough QT studies. The residual variances were extracted for each study and ECG technique. RESULTS: High-precision QT resulted in a substantial reduction in ∆QTc variability as compared to SA. A reduction in residual variability or approximately 50% was achieved in both crossover and parallel studies, both for the active comparison (drug vs. placebo) and for assay sensitivity (moxifloxacin vs. placebo) data. CONCLUSIONS: High-precision QT technique significantly reduces QT interval variability and thereby the number of subjects needed to exclude small effects in QT studies. Based on this assessment, the sample size required to exclude a QTc effect >10 ms with 90% power is reduced from 35 with SA to 18 with HPQT, if a 3 ms underlying drug effect is assumed.

Considerations for assessing the potential effects of antidiabetes drugs on cardiac ventricular repolarization: A report from the Cardiac Safety Research Consortium.

Thorough QT studies conducted according to the International Council on Harmonisation E14 guideline are required for new nonantiarrhythmic drugs to assess the potential to prolong ventricular repolarization. Special considerations may be needed for conducting such studies with antidiabetes drugs as changes in blood glucose and other physiologic parameters affected by antidiabetes drugs may prolong the QT interval and thus confound QT/corrected QT assessments. This review discusses potential mechanisms for QT/corrected QT interval prolongation with antidiabetes drugs and offers practical considerations for assessing antidiabetes drugs in thorough QT studies. This article represents collaborative discussions among key stakeholders from academia, industry, and regulatory agencies participating in the Cardiac Safety Research Consortium. It does not represent regulatory policy.

Evaluation of the QT effect of a combination of piperaquine and a novel anti-malarial drug candidate OZ439, for the treatment of uncomplicated malaria.

AIMS: The aim was to investigate the QT effect of a single dose combination regimen of piperaquine phosphate (PQP) and a novel aromatic trioxolane, OZ439, for malaria treatment. METHODS: Exposure-response (ER) analysis was performed on data from a placebo-controlled, single dose, study with OZ439 and PQP. Fifty-nine healthy subjects aged 18 to 55 years received OZ439 alone or placebo in a first period, followed by OZ439 plus PQP or matching placebos in period 2. OZ439 and PQP doses ranged from 100-800 mg and 160-1440 mg, respectively. Twelve-lead ECG tracings and PK samples were collected serially pre- and post-dosing. RESULTS: A significant relation between plasma concentrations and placebo-corrected change from baseline QTc F (ΔΔQTc F) was demonstrated for piperaquine, but not for OZ439, with a mean slope of 0.047 ms per ng ml(-1) (90% CI 0.038, 0.057). Using an ER model that accounts for plasma concentrations of both piperaquine and OZ439, a largest mean QTc F effect of 14 ms (90% CI 10, 18 ms) and 18 ms (90% CI 14, 22 ms) was predicted at expected plasma concentrations of a single dose 800 mg OZ439 combined with PQP 960 mg (188 ng ml(-1) ) and 1440 mg (281 ng ml(-1) ), respectively, administered in the fasted state. CONCLUSIONS: Piperaquine prolongs the QTc interval in a concentration-dependent way. A single dose regimen combining 800 mg OZ439 with 960 mg or 1440 mg PQP is expected to result in lower peak piperaquine plasma concentrations compared with available 3 day PQP-artemisinin combinations and can therefore be predicted to cause less QTc prolongation.

Safety, pharmacokinetics, pharmacogenomics and QT concentration-effect modelling of the SirT1 inhibitor selisistat in healthy volunteers.

AIM: Selisistat (SEN0014196), a first-in-class SirT1 inhibitor, is being developed as a disease-modifying therapy for Huntington's disease. This first-in-human study investigated the safety, pharmacokinetics and pharmacogenomics of single and multiple doses of selisistat in healthy male and female subjects. METHOD: In this double-blind, randomized, placebo-controlled study, seven cohorts of eight subjects received a single dose of selisistat at dose levels of 5, 25, 75, 150, 300 and 600 mg and four cohorts of eight subjects were administered 100, 200 and 300 mg once daily for 7 days. Blood sampling and safety assessments were conducted throughout the study. RESULTS: Selisistat was rapidly absorbed and systemic exposure increased in proportion to dose in the 5-300 mg range. Steady-state plasma concentrations were achieved within 4 days of repeated dosing. The incidence of drug related adverse events showed no correlation with dose level or number of doses received and was comparable with the placebo group. No serious adverse events were reported and no subjects were withdrawn due to adverse events. There were no trends in clinical laboratory parameters or vital signs. No trends in heart rate or ECG parameters, including the QTc interval and T-wave morphology, were observed. There were no findings in physical or neurological examinations or postural control. Transcriptional alteration was observed in peripheral blood. CONCLUSION: Selisistat was safe and well tolerated by healthy male and female subjects after single doses up to 600 mg and multiple doses up to 300 mg day(-1).

An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease.

AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.

Detection of QTc effects in small studies--implications for replacing the thorough QT study.

BACKGROUND: ECG assessment with exposure response analysis applied to data from First-in-Man studies has been proposed to replace the thorough QT study for the detection of small QT effects. METHODS: Data from five thorough QT studies, three with moxifloxacin, one study with a drug with a large QTc effect (∼25 ms) and one with ketoconazole with a smaller QT effect (∼8 ms) were used. By subsampling, studies with 6-18 subjects on drug and six on placebo were simulated 1000 times per sample size to assess whether small QTc effects using ICH E14 criteria could be excluded and the impact of sample size on the estimate and variability of the slope of the concentration/QTc relation. RESULTS: With a sample size of nine or more on drug and six on placebo, the fraction of "false negative studies" was at or below 5% with data from the studies with moxifloxacin and from the drug with a large QTc effect. With the same sample size and no underlying QTc effect (placebo), the fraction of studies in which an effect above 10 ms could be excluded was above 85%. A treatment effect in the linear concentration-effect model resulted in a lower proportion of "false negatives." Sample size had little influence on the average slope estimate of the concentration/QTc relationship. CONCLUSIONS: For drugs with a QTc effect of around 12-14 ms, exposure response analysis applied to First-in-Man studies with careful ECG assessment can be used to replace the through QT study.

Clinical ECG Assessment.

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