Meijian Zhou

Detection of QTc Effects in Small Studies—Implications for Replacing the Thorough QT Study

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.

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 Huntingtons 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 No serious adverse events were reported and no subjects were withdrawn due to adverse events.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).

A thorough QT study with dalbavancin: A novel lipoglycopeptide antibiotic for the treatment of acute bacterial skin and skin-structure infections

Two hundred healthy subjects were enrolled in a randomised, partially double-blinded, single-centre, parallel design thorough QT study to demonstrate that dalbavancin had no clinical effect on the 12-lead ECG QTc. Fifty patients in each group received either dalbavancin 1000 mg intravenous (i.v.), dalbavancin 1500 mg i.v. or placebo i.v., each infused over 30 min, or 400 mg oral moxifloxacin. Ten replicate 12-lead ECGs were extracted at pre-defined time points before and up to 24 h post dosing and at corresponding time points during baseline. Dalbavancin did not have an effect on the QTcF interval, and an effect exceeding 10 ms could be excluded at all time points after a single i.v. dose of 1000 mg and 1500 mg. The largest placebo-corrected change-from-baseline QTcF (ΔΔQTcF) was 1.5 ms in the 1000 mg dalbavancin group at 6 h and 0.2 ms in the 1500 mg group at 24 h. A small concentration-dependent effect of dalbavancin on ΔΔQTcF was identified with an estimated negative population slope of -0.0051 ms per μg/mL. Assay sensitivity was demonstrated by the effect of 400 mg moxifloxacin, which peaked at 2 h at ΔΔQTcF of 12.9 ms, with the lower bound of the 90% CI of the effect exceeding 5 ms at all three pre-defined time points. Dalbavancin did not exert a relevant effect on heart rate or PR or QRS intervals. Dalbavancin in i.v. doses up to 1500 mg did not prolong the QTc interval and had no effect on heart rate or PR and QRS intervals.

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration–response (CR) modeling applied to data from 2 multiple ascending‐dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to “bridge” pharmacokinetic and safety data between Japanese and non‐Japanese subjects (J‐MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high‐precision measurement technique and evaluated using a linear mixed‐effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was –0.00002 milliseconds per ng/mL (90%CI, –0.01019 to 0.01014 milliseconds). The highest observed Cmax was 400 ng/mL, representing a margin 8‐fold above exposures expected for the highest planned clinical dose. The model‐predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, –3.49 to 5.78 milliseconds). In neither the J‐MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early‐phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies.

Effect of Ponesimod, a Selective S1P1 Receptor Modulator, on the QT Interval in Healthy Individuals

Ponesimod is an orally active selective sphingosine‐1‐phosphate receptor 1 modulator under investigation for the treatment of multiple sclerosis. This was a single‐centre, double‐blind, randomized, placebo‐ and positive‐controlled parallel‐group study investigating the effects of ponesimod on the QTc interval in healthy individuals. A nested cross‐over comparison between moxifloxacin and placebo was included in the combined moxifloxacin/placebo treatment group. Subjects in group A received multiple doses of 10–100 mg ponesimod according to an uptitration regimen on days 2–23 and moxifloxacin‐matching placebo on days 1 and 24. Subjects in group B received ponesimod‐matching placebo on days 2–23 and were randomized to receive either a single dose of 400 mg moxifloxacin or matching placebo on days 1 and 24. The primary end‐point was the baseline‐adjusted, placebo‐corrected effect on the individually corrected QT interval (QTcI) on days 12 (after 5 days of 40 mg ponesimod) and 23 (after 5 days of 100 mg ponesimod). Ponesimod caused a mild QTcI prolongation with a largest effect of 6.9 ms (90% two‐sided confidence interval (CI): 2.5–11.3) and 9.1 ms (90% CI: 4.1–14.0) for doses of 40 mg and 100 mg, respectively. A concentration–effect analysis confirmed the QTcI‐prolonging effect of ponesimod with a shallow slope of 0.0053 ms per ng/mL. Using the concentration–effect analysis, the QTc prolongation caused by 20 mg ponesimod and the current highest therapeutic dose was predicted to be below the level of clinical concern (i.e. an upper bound of the two‐sided 90% CI of ≥10 ms).

Can Bias Evaluation Provide Protection Against False‐Negative Results in QT Studies Without a Positive Control Using Exposure‐Response Analysis?

The revised ICH E14 document allows the use of exposure‐response analysis to exclude a small QT effect of a drug. If plasma concentrations exceeding clinically relevant levels is achieved, a positive control is not required. In cases when this cannot be achieved, there may be a need for metrics to protect against false‐negative results. The objectives of this study were to create bias in electrocardiogram laboratory QT‐interval measurements and define a metric that can be used to detect bias severe enough to cause false‐negative results using exposure‐response analysis. Data from the IQ‐CSRC study, which evaluated the QT effect of 5 QT‐prolonging drugs, were used. Negative bias using 3 deterministic and 2 random methods was introduced into the reported QTc values and compared with fully automated data from the underlying electrocardiogram algorithm (COMPAS). The slope estimate of the Bland‐Altman plot was used as a bias metric. With the deterministic bias methods, negative bias, measured between electrocardiogram laboratory values and COMPAS, had to be larger than approximately −20 milliseconds over a QTcF range of 100 milliseconds to cause failures to predict the QT effect of ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. With the random methods, the rate of false‐negatives was ≤5% with bias severity < –10 milliseconds for all 5 drugs when plasma levels exceeded those of interest. Severe and therefore detectable bias has to be introduced into reported QTc values to cause false‐negative predictions with exposure‐response analysis.

Lomitapide at Supratherapeutic Plasma Levels Does Not Prolong the QTc Interval—Results from a TQT Study with Moxifloxacin and Ketoconazole

The aim of this study was to assess the effect of high plasma levels of lomitapide and its main metabolite on ECG parameters.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaines active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double‐blind, placebo‐controlled single ascending‐dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment‐emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose‐linear increases for AUC and Cmax and was slowly eliminated (mean t1/2 range, 24–30 hours). There was a concentration‐dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60‐, 120‐, and 180‐mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120‐mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure‐controlled multiple‐dose noribogaine studies are planned that will address these safety and design issues.

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) &mgr;g/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 (&Dgr;QTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected &Dgr;QTcF (&Dgr;&Dgr;QTcF) 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 studys 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.

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

ABSTRACT 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.)