Assessment of the cardiac safety and pharmacokinetics of a short course, twice daily dose of orally-administered mifepristone in healthy male subjects

Background: Mifepristone is approved to control hyperglycemia in adults with endogenousCushing’s syndrome and is described as a mildly QTc prolonging drug, based on a TQT study.The aim of the present study was to assess the effect of mifepristone on the QTc interval at plasmamifepristone concentrations exceeding those observed in the TQT study.Methods: Twenty healthy, male volunteers were given three doses of 1200 mg mifepristoneevery 12 h with a high-fat meal in a randomized, placebo-controlled 2-period crossover study.Holter ECG recordings were made on Day 1 and 2.Results: Eighteen subjects completed the study. Mean peak plasma mifepristone concentrationswere 4.01 μg/mL (CV: 31%) on the fi rst dose and 5.77 μg/mL (CV: 29%) on the thirddose. Mifepristone did not have a meaningful QTc effect. The placebo-corrected, change-from--baseline QTcF (ΔΔQTcF) was between –1.6 and 0.7 ms on the fi rst dose (upper bound of 90%CI 3.8 ms) and the largest ΔΔQTcF on the third dose was 4.9 ms (upper bound of 90% CI: 8.4 ms).Concentration effect modeling showed a slightly negative slope of –0.01 ms/ng/mL.Conclusions: Mifepristone did not cause a clinically meaningful QTc prolongation in healthyvolunteers at plasma concent rations of mifepristone and its main metabolites that clearlyexceeded those seen in a previous TQT study

Improving the precision of QT measurements

Background: Accurate and precise QT interval measurement is very important for both regulatory and drug developmental decision making. These measurements are often made using a manual or semi-automated technique, and the associated variability necessitates sample sizes of around 50 to 70 subjects in thorough QT/QTc studies. The purpose of this study was to compare the reproducibility and precision of a semi-automated (SA) method and a high-precision (HPQT) technique for ECG extraction and QT interval measurement on two thorough QT/QTc (TQT) studies conducted in compliance with ICH E14. Methods: Data from 35 healthy subjects from two different crossover TQT studies on treatment with placebo and moxifloxacin was analyzed. Both methods examined the RR and QT intervals measured in lead II or the lead with the highest quality T-wave on a single beat basis using the QT algorithm included in the COMPAS software package. ECGs were measured at a protocol-specific timepoint. Results: The effect of moxifloxacin on the QTc interval was highly reproducible in the two studies, and assay sensitivity was met with both methods. Pairwise comparison of QTcF values between methods demonstrated high agreement with no bias, small mean differences (below 1.5 ms) and narrow limits of agreement. HPQT improved the precision of the QTc measurement by 31% in Study I (standard deviation of DQTcF: SA 8.9 ms; HPQT 6.3 ms) and by 15% in Study II (SD: SA 9.7 ms; HPQT 8.3 ms). Conclusions: The HPQT QT measurement technique detected the effect induced by moxifloxacin with the same accuracy as SA techniques, and with clearly improved precision. More precise QTc measurement has important implications in terms of lowering the likelihood of false positive results and/or reducing the sample size in TQT studies, as well as improving the utility of QT assessment in early clinical development. (Cardiol J 2011; 18, 4: 401–410

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.</p

Comparing QT interval variability of semi-automated and high precision ECG methodologies in 7 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 ΔQTc 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

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 IC(50) 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

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