P31-07 Methods for long-term intravenous infusion of drugs while assessing local tolerance in rats and rabbits

Assessing the local tolerance of parenterally administered drugs is a crucial step in the preclinical evaluation of new drugs. This administration route is particularly relevant when oral delivery is unsuitable. While local tolerance assessment is relatively straightforward for subcutaneous injections, intravenous (iv) injections present greater risks of potential vascular irritation or endothelial damage, particularly when administered over longer periods. This study presents methods for evaluating the local tolerance of iv injected drugs, delivered using implantable infusion pumps in rats or vascular access buttons (VAB) in rabbits to facilitate long-term drug administration. Male Sprague-Dawley rats were implanted subcutaneously with iPRECIO® Pumps (SMP-200) with a catheter inserted into the jugular vein. The infusion rate started at 1 µL/h (recovery period) and increased to 30 µL/h (continuous infusion of saline over 3 days). Male New Zealand albino rabbits underwent surgical placement of a catheter in the jugular vein connected to a subcutaneous VAB (VABR1B/22) for repeated iv bolus injections. After recovery, the rabbits received a single iv bolus of saline (1 mL) for 3 consecutive days. Clinical observations included erythema, swelling, necrosis and ulceration at the infusion sites. At the end of the 3-day injection period, the catheterized jugular vein, adjacent perivascular tissue, and the contralateral control jugular vein (not catheterized) were collected and fixed in 10% neutral formalin. The tissues were separated in four blocks from the catheterized jugular vein (indwelling of the catheter into the vein and end of catheter tip: 0, 0.5 and 1 cm from the extremity) or one block from the contralateral vein. Collected samples were embedded in paraffin, sectioned at 4 µm thickness and stained with hematoxylin & Eosin for histopathological evaluation. No clinical observations of intolerance were observed in both species, while histopathological findings showed vascular and perivascular inflammation, primarily at the catheter entry site (considered to be secondary to the surgical implantation of the catheter), with severity decreasing at greater distances from the end of the catheter tip. The non-catheterized jugular vein remained histologically unremarkable, confirming that the inflammatory response was localized and associated with catheter presence. These findings confirm that implantable pumps in rats and VABs in rabbits offer reliable methods for long-term infusion studies, allowing for the assessment of drug-related local tolerance independent of the infusion technique. These methods further enable the precise and continuous delivery of drugs, minimizing handling stress and allowing for long-term assessment of potential injection site reactions. The findings reinforce the importance of species-specific considerations in preclinical studies and highlight the need for optimized infusion protocols to minimize local tissue reactions.