SURGICAL AND NON-SURGICAL DRUG DELIVERY METHODS IN MINISWINE MODELS

Scientific Poster
Surgical and Non-Surgical Drug Delivery Methods in Miniswine Models - SciPos111

Abstract

Miniswine models have evolved to become very important in the preclinical evaluation of drugs. Moreover, translational medicine programs are confirming that the minipig is the model of choice for pharmacokinetics assessment, in addition to its role in the evaluation of drug efficacy and safety.

Miniswines provide numerous advantages when conducting pharmacokinetics (PK) studies: their body size allows numerous blood samples with large volumes, their smaller body size as compared to domestic pigs facilitates their handling, their anatomy and physiology sizeproportional when compared to humans and biotransformation factors (e.g. CYP450 enzymes) are similar to humans.

However, although most classical routes of exposure are possible in the miniswine, some do require the use of specialized drug delivery methods.

Purpose: In the present report, we will illustrate selected surgical and nonsurgical drug delivery methods that can be applied to the minipig amongst the broad available array of delivery devices.

Methods: For example, vascular access in minipigs includes surgical and non-surgically placed catheters or direct venipuncture. Subcutaneous vascular access ports (VAPs) are placed surgically into the external jugular vein and may be placed bilaterally to facilitate both dosing and sampling. Repeated access of the port through the skin is possible using a specially designed needle (Huber point). Port useful lifetime in minipigs can be quite long but good port maintenance is essential. Troubleshooting of port malfunction includes assessment for infection, complete occlusion or partial withdrawal occlusion (PWO or fibrin flap).

Results: In addition, we will describe the feasibility and ease of use of the following devices:

Surgical Delivery Methods: Intestinal Delivery Cannulas, Femoral Catheters, Cardiac or Pericardial Catheters, Drug-Eluting Devices.

Non-Surgical Delivery Methods: Percutaneous Catheters, Infusion Catheters, Topical Delivery Pumps, Endoscopic Drug Delivery, Dermal Patches, Intrathecal and Intracisternal Catheters.

In conclusion, the use of the miniswine has been validated for pharmacokinetic modeling over the years and most drug delivery methods are compatible if adapted to their anatomy and physiology.

Authors

Buckman K1, Brown L1,2, Hanks BC1, Stricker-Krongrad A1, Sword M1, Madsen T1, Lawson C1, Brocksmith D2, Liu J1, Bouchard GF1,2
¹Sinclair Research Center, LLC ²Sinclair BioResources, LLC, Auxvasse, MO, USA

Introduction

This poster outlines the valuable nature of miniature swine to pharmacology and illustrates selected surgical and nonsurgical drug delivery methods amongst the broad array of available drug delivery methods. Miniswine models have evolved to become more important to preclinical drug development, specifically pharmacokinetics. Multiple standard routes (po, iv, dermal, id, sc, transmucosal, gi, csf or intracisternal, intrathecal, subdural, intraocular, intravesicular, intranasal, intravaginal, per rectal) are possible. Common and unique drug delivery options include both surgical and non-surgical delivery methods. Selections included herein are: Surgical Delivery Methods: VAPs, intestinal Cannulas, Femoral caths, cardiac or intrapericardial caths, drugeluting stents; Non-Surgical Delivery Methods: Percutaneous caths, Infusion caths, Topical delivery pumps, Endoscopic GI drug delivery, dermal patches, iontophoresis, CSF puncture & intracisternal drug delivery.

Methods

Selected surgical and non-surgical methods with salient characteristics are presented in Table 1 (right). These drug delivery options make miniswine inherently valuable models.

Successful vascular access in miniswine includes proper selection of method, good technical skills for surgery or catheter placement, proper maintenance procedures, and knowledge for troubleshooting problems when they arise. The vascular access options are usually selected based on length of the study. Vascular access in minipigs includes surgical and non-surgically placed catheters or direct venipuncture. Subcutaneous vascular access ports (VAPs) are normally placed surgically into the external jugular vein and may be implanted bilaterally to facilitate both dosing and sampling. The port is usually placed under the skin of the side of neck and the catheter tubing is run under the skin to the ventral neck where it is secured to the lumen of the jugular vein. The VAP must be properly cared for to ensure the health of the animal and the patency of the port. Repeated access of the port through the skin is possible using a specially designed needle (Huber point). Currently we have ~300 ported minipigs in house; ~190 of those are diabetic. Port useful lifetime is usually >1year with moderate use in our laboratory, but good port maintenance is essential. VAP life also depends greatly upon multiple other variables: number times the port is accessed, age the pig is ported, where the port is placed, what is put into the port, etc. Some VAPs function well even after 2 years following strict aseptic procedures, good maintenance, and TLC by well-trained technicians. Aseptic technique is very important and essential for use of VAPS. The VAP is adequately flushed with heparin-saline solution and locked with TCS. Approximately 2cc (depends on port and catheter size) of TCS lock solution - Taurolidine-Citrate Solution, TCS-04™ (Access Technologies) is recommended for best results. Troubleshooting of port malfunction includes assessment for infection, complete occlusion or partial withdrawal occlusion (PWO or fibrin flap). The PWO category is a common troublemaker occurring in approximately 10% of problem VAPs.

Surgical Delivery Methods: VAPS, intestinal cannulas, femoral caths, cardiac or intrapericardial caths, drug-eluting stents.

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Discussion

Vascular access in minipigs includes surgical and non-surgically placed catheters or direct venipuncture. Subcutaneous vascular access ports (VAPs) are placed surgically into the external jugular vein. Essential aspects for successful VAP use in miniswine include use of catheter and VAP materials with low potential for tissue reactivity, sterile procedures when implanting, use of atraumatic catheter tips, reserve catheter length for animal growth if implanted at young age, use of catheters with retention beads, regular flushing and maintenance requirements, anticoagulants, diagnostics, and troubleshooting. Troubleshooting of port malfunction includes assessment for infection, complete occlusion or partial withdrawal occlusion (PWO or fibrin flap). Any major error in port use or maintenance can result in permanent VAP loss or failure. Ports are only as good as the proper placement and maintenance and care.

References

  1. Swindle MM. Swine in the Laboratory: Surgery, Anesthesia, Imaging, and Experimental Techniques, CRC Press, 2007.
  2. McAnulty PA, et al (Eds). The Minipig in Biomedical Research, CRC Press, 2012.
  3. Swindle MM et al. 2005. Vascular access port (VAP) usage in large animal species, Contemp. Top. Lab. Anim. Sci. 44(3):7-17.

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