Assessment of sensitivity of invasive telemetry to detect a prolongation of the QTc interval in the conscious Göttingen minipig using moxifloxacin as a positive control

Abstract

ICH E14/S7B guidelines evolved to re-consider the need to conduct Thorough QT trials (TQT) to evaluate the clinical “QT risk”, based on the outcome of non-clinical ECG investigations in telemetered non-rodents (“CV assay”), using an integrated risk assessment. In addition to generate standard QT/QTc interval duration, CV assays should now provide values for Least Significant Difference (LSD) and Root Mean Square Error (RMSE) as indices of study sensitivity, using ANOVA on super-interval (SI), performed on time-matched, vehicle-subtracted QTc values (DQTc), and a cross-over, Latin square (XO-LS) design. If neither QTc prolongation nor hERG inhibition are detected, with demonstration of suitable study sensitivity, drug developers may apply for a waiver, for not conducting TQT, thereby reducing drug exposure of healthy volunteers and allowing faster progression of promising therapeutics. Minipigs were selected as an increasingly used non-rodent species, better ethically accepted than NHPs and dogs. However, by comparison with ample information gathered from the latter two species, data on the ability of minipig CV assays to detect QTc prolongation using a XO-LS design are scarce. Therefore, in agreement with our Ethical Committee, we applied XO-LS design to test QT‑prolonging effects of moxifloxacin at 10, 30, and 100 mg/kg, given orally and once weekly to four M11-implanted male Göttingen minipigs. Arterial blood pressure, body temperature, ECG, and activity were recorded for 1.5 h predose and 24 h postdose. Moxifloxacin dose‑dependently prolonged Holzgrefe-corrected QT interval (QTcH) for 24 h, with maximum increases in DQTcH of 15 msec at 10 mg/kg (SI: [0 h–4 h]), 20 msec at 30 mg/kg (SI: [8 h–18 h]) and 71 msec at 100 mg/kg (SI: [8 h–18 h]); in-study sensitivity values for DQTcH LSD and RMSE were 24 msec and 13 msec, respectively. Moxifloxacin exerted no relevant effects on the other telemetry parameters. This study demonstrates the capacity of our facility to conduct a cross-over, Latin square study design with a sensitivity high enough to detect drug-induced QTc prolongation in minipigs, and further supports their use for CV assays, as an alternative species to dogs and NHPs, in the context of regulatory evolutions about human QT risk evaluation.