Minimally Invasive Endoscopic Techniques Allow Serial Tissue Visualization and Sampling for Pharmacokinetics and Safety Studies in Large Animal Models of Vascular Disease and Intervention
O. A. Chiesa, W. F.. Pritchard, T. L.. Murray, A. D.. Shah, J. W.. Karanian, Laboratory of Cardiovascular and Interventional Therapeutics, DB/OSEL/CDRH, MRC, MODII, Laurel MD 20708
Background: Standard pre-clinical pharmacokinetics studies (temporal and spatial drug distribution) generally require use of multiple animals in which the animals are dosed then sacrificed at different time points for tissue collection. Endoscopic surgical techniques allow access to the chest and major organs as a minimally invasive, survival procedure. Since major surgical exposure of the target tissue is avoided, animals may be studied repeatedly, reducing the number of animals required for collection of critical drug safety data.
Methods: Mature domestic swine underwent diagnostic coronary angiography. Using a novel microsyringe catheter, fluorescently labeled paclitaxel was delivered to the perivascular space by injection from within the coronary artery. The animals were allowed to recover. From 1 to 28 days later, each animal again underwent diagnostic angiography. The abdomen and chest were accessed using endoscopic techniques.
Results: Coronary angiography and local drug delivery was successfully performed in all animals. At endoscopy, the coronary vessels could be directly observed. In the 1 day animals, local hemorrhage at the drug delivery site could be identified through the pericardium. In the 30 day animals no hemorrhage was noted utilizing this approach. Catheter placement into the pericardial space allowed sampling of pericardial fluid. Entry into the pericardial space allowed direct inspection of the epicardium and coronary vessels.
Conclusions: Minimally invasive thoracoscopic access allows multiple observations of induced lesions and serial tissue sampling, providing more efficient study of the pharmacokinetics of locally delivered drugs. This may serve as a preclinical development tool for the evaluation of therapeutic devices and combination products, enhancing the data collected while reducing the number of animals required for preclinical safety studies.