Estimation of respiration rate from nonclinical telemetry ECG data.

Assays to assess respiratory function are included in the ICH S7A guidance for Safety Pharmacology, which identifies the core in vivo studies required to evaluate safety prior to First in Human (FIH) dosing. This requirement is most commonly met using dedicated stand-alone rodent respiratory studies that require additional studies and increased resources. More importantly, the demonstrated transitional value of dedicated respiratory endpoints to predict risk and improve FIH safety is lacking. As such, alternative approaches that utilize commonly collected signals from cardiovascular assessment studies, such as electrocardiograms (ECG), to calculate respiration rate (RespRate) as a biomarker of potential adverse effects are becoming increasingly relevant. In this study, we implement three algorithms developed to estimate ECG-derived RespRate (EDR) in humans on preclinical ECG data collected from dogs. We then compare EDR to the benchmark direct measure of RespRate derived from telemetry intra-thoracic pressure (ITP) sensors in 19 recordings. EDR obtained using the moment-based and principal component-based algorithms was not significantly different from the benchmark, based on a TOST (two one-sided tests) analysis with an equivalence margin of five breaths/min, in 100% and 89% of animals respectively. Furthermore, in a positive control study administering Theophylline, the PCA method detected a drug-induced increase in RespRate also present in the ITP data. Thus, EDR may provide a potential alternative to stand-alone respiratory assays, but further evaluation across a broader range of respiration changes, subjects, and ECG hardware is needed to establish the robustness of these algorithms.