Validation of in vivo QT ICH E14/S7B Q&A guidance in minipig

Abstract

The E14/S7B Q&A guidelines introduce the concept of “double negative” (negative hERG and negative in vivo QTc) non-clinical data which can be used along with negative Phase 1 clinical QTc data to substitute for a clinical Thorough QT study in specific cases (Q&As 5.1 and 6.1). The non-clinical data are to be generated using “best practice” designs in order to support data quality and consistency across the industry. For the in vivo QT assay, best practice recommendations require characterization of individual study sensitivity, verification of independence QTc from heart rate, demonstration of test facility sensitivity and pharmacological translation to human using a positive control. We have previously validated E14/S7B Q&A compliant in vivo QT assays in dog and non-human primate. The objective of this work was to perform the validation in the minipig as the third non-rodent species commonly used for cardiovascular safety assessment. A positive control telemetry study was performed with moxifloxacin (30, 120, 300 mg/kg) using a double Latin square crossover study design (n = 8), followed by an ascending dose design (n = 5). A single PK sample was drawn during the telemetry phase, and a separate full PK phase was included at all dose levels for PK/PD assessment to determine translation to human. Moxifloxacin-induced increases in QTc were observed, with a maximal increase at the highest dose of 86 and 67 msec for the double cross-over and ascending dose designs, respectively. Smallest statistically detectable differences (SSDD) for QTc were 11 msec for the double cross-over and 10 msec for the ascending dose design. Based on the free plasma exposures and magnitude of the QTc effects from the crossover data, a 10 msec effect was observed at 0.77× of the free moxifloxacin concentration known to produce a 10 msec QTc effect in human. In conclusion, we have validated an E14/S7B Q&A compliant in vivo QT assay in the minipig for both cross-over and ascending dose designs and shown good translation to human, completing the Labcorp™ offering for in-vivo E14/S7B Q&A compliant studies.