Near‐Thorough QT Study as Part of a First‐In‐Man Study

Malik, Marek; Hnatkova, Katerina; Ford, John W.; Madge, David J.

doi:10.1177/0091270008323261

Cited by 29 publications

(24 citation statements)

References 25 publications

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“…Only one Holter-extracted ECG out of more than 4,000 revealed an increase from baseline of 60 ms, but remained within the normal ranges. The 24 h Holter recordings were analysed using an analytical method similar to that of Malik et al [20] using five replicates per time point; double delta from baseline for corrected QT (QTc) interval and individual corrections based on QT/RR pattern at D-1.…”

Section: Resultsmentioning

confidence: 99%

Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies

et al. 2014

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Background and ObjectivesFexinidazole is a 5-nitroimidazole recently included in a clinical efficacy trial as an oral drug for the treatment of human African trypanosomiasis (HAT). Preclinical studies showed it acts as a pharmacologically active pro-drug with two key active metabolites: sulfoxide and sulfone (the most active metabolite). The present studies aimed to determine the best dose regimen for the treatment of stage 2 sleeping sickness patients, which could eventually also treat stage 1 patients.MethodsFexinidazole was assessed in 154 healthy adult male subjects of sub-Saharan African origin. Three initial first-in-human studies and two additional studies assessed a single ascending dose and multiple ascending doses (both under fasted conditions), tablet versus suspension formulation and food effect (fasted vs. high-fat meal and field-adapted food), and multiple ascending doses with a loading dose regimen under fed conditions.ResultsFexinidazole was well-tolerated in a single dose from 100 to 3,600 mg, with quick absorption of the parent drug and rapid metabolism into sulfoxide [time to maximum concentration (tmax) 2–5 h] and sulfone (tmax 18–24 h). The tablet formulation was approximately 25 % less bioavailable than the suspension, and food intake increased drug absorption and plasma concentrations of fexinidazole and its two metabolites by approximately 200 %. Fourteen-day multiple ascending dosing administered up to 3,600 mg/day in fasted conditions showed that fexinidazole was generally well-tolerated (mild to moderate, spontaneously reversible drug-related adverse events). Following the high-fat food effect finding, another study was conducted to evaluate the impact of a low-fat regimen closer to that of the target population, showing that the type of meal does not influence fexinidazole absorption. The last study showed that a loading dose of 1,800 mg/day for 4 days followed by a 1,200 mg/day regimen for 6 days with a normal meal provided the desired exposure of fexinidazole and its metabolites, particularly sulfone, with good tolerability. Based on preclinical evidence from a chronic infection mouse model, systemic drug concentrations obtained are expected to be clinically effective in stage 2 HAT.ConclusionsThese studies show that fexinidazole can be safely assessed in patients as a potential oral cure for both stages of HAT.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-014-0136-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Determination of an Optimal Dosing Regimen for Fexinidazole, a Novel Oral Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Studies

et al. 2014

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“…Because the interpretation is driven by the upper confidence interval rather than by the mean QTc change, the sample size of a TQT study is high [20]. The sample size necessary for a TQT study depends on the assumed within-subject variance based on the number of ECGs to be used and the maximum allowable placebo-adjusted true mean change from baseline increase in QTc (10 ms according to the E14 guidance).…”

Section: Discussionmentioning

confidence: 99%

Moxifloxacin versus placebo modeling of the QT interval

Urien

2012

J Pharmacokinet Pharmacodyn

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The objectives were to develop a population model for placebo-corrected moxifloxacin QT interval in healthy subjects using non-linear mixed effects modeling and to examine effect of covariates on the observed QT. Based on the parameters of interest, optimizations of observation times and number of subjects were proposed. A pool of four thorough QT studies was used, representing 99 subjects receiving placebo and moxifloxacin. The data was modeled using Monolix. The placebo effect on QT was satisfactorily described using a 2-oscillator model. It reflected the circadian rhythm variability which is taken into account when assessing the time-matched mean difference on QT between treatment and baseline. Based on this model, the moxifloxacin effect on QT was satisfactorily described by the same equation with the adjunct of a direct and proportional drug concentration-effect. The Emax model provided the best description of the effect. The unique covariate was gender for both baseline QTc and individual heart rate correction factor. The present design included up to 16 observations for pharmacodynamics. Using this model, 9 observation times for pharmacodynamics provided satisfactory estimates for the parameters of interest (Emax). With 15% precision limit on Emax, 60 subjects was optimal. The simultaneous placebo-moxifloxacin QT model proposed is an interesting alternative to the ICH E14 guideline in assessing QT prolongation effect. This approach provides accurate information over a range of concentrations using different relationships (slope or Emax models) to quantify the drug-response relationship versus placebo. This allowed optimizing the observation times and number of subjects.

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“…This is accomplished by a "thorough QT" study. The most common design assesses the QT intervals during a four-arm trial: 1) steady state of usual drug dosages; 2) steady state of higher dosages (or during metabolic inhibition); 3) a drug known to produce a small QT interval increase, most often the antibiotic moxifloxacin, as a positive control; and 4) placebo (Shah, 2005a;Bloomfield et al, 2008;Malik et al, 2008;Sethuraman and Sun, 2009). Because QT is dependent on rate, QT values are rate-corrected, generally using the Fridericia formula.…”

Section: F Impact Of Qt Prolongation On Drug Developmentmentioning

confidence: 99%