Katerina Hnatkova1, Donna Kowalski2, James J Keirns2, E Marcel van Gelderen3, Marek Malik4. 1. Imperial College, London, England. 2. Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Inc., Northbrook, IL, USA. 3. Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, The Netherlands. 4. St. Paul's Cardiac Electrophysiology and Imperial College, London, England. Electronic address: marek.malik@btinternet.com.
Abstract
BACKGROUND: Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established. METHODS: Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males. During each of the baselines, subjects were fasting in the morning and were served standardized lunch. Heart rates and QTc intervals were measured during repeated time-points throughout each study day. Two investigations were performed. In the first investigation, 3 heart rate and QTc measurements 1, 2, and 3h after lunch were averaged in each subject and corrected for the morning fasting baseline. Reproducibility of heart rate and QTc changes after the meal on different days X and Y was assessed by normalized repeatability coefficients 2*|MX-MY|/|MX+MY|, where MX and MY are measurements in the same subject on days X and Y, respectively. These were compared for heart rate and QTc changes after meal for different pairs of baseline days. In the second investigation, 36 females and 41 males were considered who received moxifloxacin during the source thorough QT study. The QTc increases after moxifloxacin were expressed by averaging 3 time-point values and corrected for placebo QTc values measured 25days apart. In the same subjects, QTc readings after lunch were also corrected for fasting baseline readings 25days apart. QTc responses to moxifloxacin and to meal intake were compared. RESULTS: Repeatability of QTc decreases after meal was significantly (p<0.0000001) poorer than that of heart rate increases after meal. Of the subjects receiving moxifloxacin during the study, 6% did not show QTc prolongation on moxifloxacin while 39% have not shown QTc shortening after lunch (p<0.00001). CONCLUSION: The reproducibility of QTc changes after meal is limited. The power of proving QTc assay sensitivity by the detection of QTc changes after meal is poorer than the power of the standard moxifloxacin-based assay sensitivity.
BACKGROUND: Detection of QTc decreases after meal intake was proposed as a possible proof of assay sensitivity in studies of drug-induced QTc changes. However, day-to-day reproducibility of QTc decreases after meal intake has not been established. METHODS: Holter recordings were available from 4 different baseline drug-free days of a thorough QT study in 157 females and 164 males. During each of the baselines, subjects were fasting in the morning and were served standardized lunch. Heart rates and QTc intervals were measured during repeated time-points throughout each study day. Two investigations were performed. In the first investigation, 3 heart rate and QTc measurements 1, 2, and 3h after lunch were averaged in each subject and corrected for the morning fasting baseline. Reproducibility of heart rate and QTc changes after the meal on different days X and Y was assessed by normalized repeatability coefficients 2*|MX-MY|/|MX+MY|, where MX and MY are measurements in the same subject on days X and Y, respectively. These were compared for heart rate and QTc changes after meal for different pairs of baseline days. In the second investigation, 36 females and 41 males were considered who received moxifloxacin during the source thorough QT study. The QTc increases after moxifloxacin were expressed by averaging 3 time-point values and corrected for placebo QTc values measured 25days apart. In the same subjects, QTc readings after lunch were also corrected for fasting baseline readings 25days apart. QTc responses to moxifloxacin and to meal intake were compared. RESULTS:Repeatability of QTc decreases after meal was significantly (p<0.0000001) poorer than that of heart rate increases after meal. Of the subjects receiving moxifloxacin during the study, 6% did not show QTc prolongation on moxifloxacin while 39% have not shown QTc shortening after lunch (p<0.00001). CONCLUSION: The reproducibility of QTc changes after meal is limited. The power of proving QTc assay sensitivity by the detection of QTc changes after meal is poorer than the power of the standard moxifloxacin-based assay sensitivity.
Authors: Irena Andršová; Katerina Hnatkova; Martina Šišáková; Ondřej Toman; Peter Smetana; Katharina M Huster; Petra Barthel; Tomáš Novotný; Georg Schmidt; Marek Malik Journal: Sci Rep Date: 2021-07-12 Impact factor: 4.996