Influence of surgically implantable telemetry solutions on in-life and post-mortem toxicology endpoints

摘要

Introduction: Understanding the appropriate application of telemetry and other technologies for nonclinical investigation of functional safety issues in the context of ongoing toxicology evaluations is a current industry challenge. One major issue is related to the potential impact of surgical implantation of a telemetry device on contemporarily established measures of drug toxicity, and potential for confounding pathological issues related to the systemic and local response of the experimental animal to the presence of a foreign body. This study was designed to evaluate the potential local and systemic impact of different implanted telemetry devices with varying requisite degrees of surgical complexity on general toxicology study endpoints. Methods: Sixteen male beagle dogs 1) no surgical instrumentation [n = 4], 2) Jacketed External Telemetry (JET) with femoral artery blood pressure implant (PA-C10 LA) [n = 4], or 3) fully implantable (DSI-D70-CCTP) devices [n = 8], were assigned to experimental groups and evaluated within the context of a standard repeat-dose toxicology design to determine the potential impact of these treatments on routine in-life and post-mortem toxicological endpoints. Results: Device implantation, regardless of the level of invasiveness/complexity was without effect on any in-life safety parameter, including clinical chemistry and hematology, assessed in the experimental design. Histopathological findings were limited to the expected, primarily minimal to mild localized effects characteristic of a foreign body reaction (fibrosis, inflammation) in the area immediately in contact with the body of the transmitter device and associated sites of ECG lead and pressure catheter interface with local tissues. Discussion: This study represents the first definitive evaluation of the influence of variably invasive telemetry device implantation on standardized, essential toxicology endpoints in the context of a simulated repeated dose experimental design. The data suggest that, when carefully evaluated, the local effects of implanted telemetry devices can be managed in the context of a standard Investigational New Drug (IND)-enabling toxicology study. This study provides support for the potential incorporation of unrestrained cardiovascular assessments via implanted or external telemetry into standard multi-dose toxicology studies.