A retrospective review of the effects of moxifloxacin in dogs at four different test sites

Abstract

With adoption of the ICH E14/S7B Q&A best practice guidance, non-clinical cardiovascular data sets can be used in place of clinical data to support of a TQT waiver application. However, as part of this guidance each laboratory is required to demonstrate adequate sensitivity of their specific in vivo model using a known positive control agent (e.g., moxifloxacin) or through retrospective review of historical data sets. These requirements raise questions around how often a positive control study should be conducted and how stable the effects of moxifloxacin are across multiple laboratories. In the current review we assessed the effects of moxifloxacin, in dogs, from four test sites. All four laboratories administered moxifloxacin at 10, 30 and 90 mg/kg by oral administration and evaluated cardiovascular parameters for 24 h post administration. The study designs between labs differed slightly, with test sites 1 and 2 utilizing a traditional 4*4 cross-over design in a single housing paradigm, test site 3 utilizing a 4*4 cross-over design with paired housing, and test site 4 utilizing a modified cross-over design with only two dose levels assessed per day. Additionally test site 1, used female animals, with other sites using males. Concentration-QTc modeling was also conducted at two sites with minor site-to-site variances in the blood sample collection methods and timing observed. All sites illustrated comparable dose dependent increases in QTc prolongation. Administration at 90 mg/kg resulted in QTc prolongation of up to 30.5, 35.6 33.2 and 31.2 msec, relative to control, at test sites 1, 2, 3 and 4 respectively. Whilst a review of study specific least significant difference, ranged from 6.4 to 11.1 msec, and residual error ranged from 4.1 to 6.4 msec; with conc-QT modeling, at test site 1 and 4,indicating that concentration ranges of 2867 to 2937 ng/ml would be expected to induce a 10-msec prolongation. These results indicate that when following best practice methodologies, dog CV models are highly consistent, independent of laboratory. This suggests that repeated administration of moxifloxacin across all laboratories is not essential and reliance on historical data sets alone should suffice to confirm model suitability.