Rabbits are commonly used for pharmacokinetic (PK) and toxicokinetic (TK) studies in the research setting, requiring repetitive venipuncture, which can be challenging in this species. The auricular vessels are commonly used for venipuncture in rabbits. The repetitive access of these delicate vessels can lead to trauma such as hematomas causing venipuncture to become more challenging as the study progresses. In turn, this leads to missed time points or insufficient blood samples. Surgical models for chronic vascular access in rabbits are common throughout the industry. Common models include exteriorized vascular catheters and implanted vascular access ports. However, these implants come with their own complications and restrictions when used in rabbits. Therefore, the authors evaluated the use of a vascular access button (VAB), an implant commonly used in small rodents, as a refinement to the current chronic models in use in the industry. Seventeen rabbits were implanted with either single or dual channel VABs. The catheters were implanted in the femoral artery and/or vein and then tunneled subcutaneously to the button on the dorsal thoracic area. Overall, the results were outstanding, and an established model was created. The average patency rate was 316 days with several implants still patent after 2 years. The authors feel the implantation and use of a vascular access button in rabbits for routine PK studies is an excellent refinement. The rabbits tolerate the buttons extremely well with minimal issues. The patency rate is equal to or better than vascular access ports and when used with the tethering system, provides a hands-off method for blood collection and intravenous administration in rabbits during PK studies.

Background: Biologic therapeutics constitute up to 30% of all drugs approved from 2010 to 2018 and represent a continuous growing market. In contrast to small molecules, biologic therapeutics (>1 kDa MW) are administered parenterally or intravenously due to poor bioavailability when administered orally. The absorption and disposition of biologics that are administered subcutaneously may be absorbed via lymphatic or blood capillaries. Methods: To understand the absorption and distribution of biotherapeutics via the lymphatic system a surgical model was developed in the cynomolgus macaque (Macaca fascicularis) to allow for frequent and chronic collection of lymph fluid. Additionally, the model allowed for the recirculation of the lymph fluid into the blood stream providing true physiologic redistribution of the biologic drug from the bloodstream back into the lymph. Results: To our knowledge, models of lymphatic duct catheterization with recirculation in the NHP have not been reported. The model consisted of two surgically implanted catheters, one in the thoracic lymph duct and one in the azygous vein. These two catheters were then exteriorized and connected to each other to allow for recirculation of lymph back into the venous blood stream. The exteriorized catheters were protected within the pocket of a jacket. Thirty-one surgical procedures were performed with an overall success rate of 70%. Unsuccessful attempts were related to anatomical differences where the lymphatic duct was either not identifiable (n = 3) or too small to catheterize (n = 6). The patency rate was 90% instrumented animals for at least 24 h, up to 168 h. Conclusion: We present the surgical technique, complications, and refinements which resulted in a reliable and reproducible model in the nonhuman primate for the chronic collection and recirculation of lymphatic fluid.

The 33rd Annual Meeting of the Academy of Surgical Research was held from October 4 to 6, 2017 in Las Vegas, Nevada. The meeting welcomed >160 participants from 27 different states and five countries representing the organization's diverse membership of technicians, veterinarians, medical doctors, and biomedical researchers. The Academy's annual meeting is focused on promoting the advancement of professional and academic standards, education, and research related to the art and science of experimental surgery. Presentations included four invited keynote speakers and 30 selected lectures and posters. A primary strength of the meeting was that lectures were complimented with practical sessions that included four wet lab and two dry lab half-day courses. Likewise, participants were brought together in workshops emphasizing research workflow from starting experimental design to readying results for publication. In this report, we present the highlights from this meeting and some selected abstracts that illustrate the diverse scientific expertise of the Academy and progress in surgical research.

The 34th Annual Meeting of the Academy of Surgical Research was held from September 26-28, 2018 in Charleston, South Carolina. The Academy's community joins together at the annual meeting to promote and advance professional and academic standards, education, and research related to the art and science of experimental surgery. Over 150 participants from 26 different states and 4 countries attended and reflected the diverse membership of technicians, veterinarians, medical doctors, and biomedical researchers and broad network between industry and academia. Presentations included 4 invited keynote speakers and together with breakout and poster sessions. These tracks were complimented with practical courses that included wet labs for participants to practice hands-on surgical technique and dry lab workshops covering surgical anesthesia as well as proper study design and path to publication. In addition, social activities helped attendees to connect with potential mentors and collaborators at the meeting. We present the highlights from this meeting in this report together with selected abstracts that illustrate the diverse scientific expertise of the Academy and promising new surgical research.

Variability in oral absorption in pre-clinical species makes human dose projection challenging. In this study, we investigated the mechanistic basis of variability in oral absorption of a model hydrophobic compound with pH-dependent solubility, BMS-955829, after oral dosing in rats, dogs, and cynomolgus monkeys. The contribution of regional absorption to pharmacokinetic variability was assessed in ported monkeys by direct intraduodenal and intraileal administration. The effect of BMS-955829 on gastric emptying and intestinal motility was investigated by radiography after co-administration of barium. BMS-955829 exhibited species dependent oral bioavailability, with high variability in monkeys. During regional absorption studies, highest rate of drug absorption was observed after direct intraduodenal administration. Radiography studies indicated that BMS-955829 slowed gastric emptying and intestinal motility. The effect of rate and site of drug release on oral exposure was studied using different drug product formulations. Reducing the rate of drug release reduced oral exposure variability without compromising exposure in cynomolgus monkeys. This effect was likely mediated by avoidance of rapid initial absorption and drug effect on gastric emptying and intestinal transit within the biorelevant timeframe. Thus, drug release rate can modulate the effect of physiological factors on variability in the oral absorption of sensitive compounds.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by an excessive production of extracellular amyloid plaques and intracellular neurofibrillary tangles in the brain. Studies have shown that concentrations of tau and amyloid protein (β-amyloid (Aβ)) are altered in the cerebrospinal fluid (CSF) of patients with AD. In an effort to support the investigation of specialized CSF biomarkers, a reliable and reproducible chronic system was developed to collect lumbar CSF from conscious dogs. Several nonsurgical and surgical procedures have been published for accessing lumbar CSF. We elected to use a lumbar catheter with a vascular access port to collect lumbar CSF. Although the surgical model is not novel, we evaluated various modifications to the procedure and maintenance to increase patency of chronic indwelling lumbar CSF catheters. Different types of catheters were evaluated, and for our purposes a 3.5 Fr open-ended polyurethane catheter was selected. With our final modified surgical procedure and catheter maintenance program, 67% remained patent for longer than 30 days for the first surgery and 86% remained patent for longer than 30 days if a repair or replacement surgery was performed. Based on the results of the proof of concept studies, our model proved to be useful for single and multiple dose pharmacokinetic studies in a search for effective Alzheimer's disease treatment.

Target validation or demonstration of efficacy requires adequate in vivo exposure of tool molecules to determine their activity in order to validate the model or show the potential usefulness of the pharmacophore. Early discovery work is often carried out with compounds which possess undesirable PK properties in small rodents where the discovery formulation scientist is often forced to dose 2-4 times per day. Gastric retentive formulations in small rodents (rats/mice) could enable increased duration of exposure for compounds with narrow absorption windows or increased residence time for compounds with targets located in the GI tract. The aim of this work is to establish an easily administered gastric retentive gel for rodents in situ using a mixture of sodium alginate and karaya gum. Feasibility studies were conducted in Sprague-Dawley rats using barium sulfate as a radio-opaque tracer. The results show that gastric retention of barium was achieved for rats dosed with the gel formulation relative to a barium suspension. The gastric residence time of the gel varied from 1h to >8h (n=3). The data suggest that sodium alginate/karaya gum gels may be a useful tool to achieve gastric retention in rodent studies.