Opportunities and challenges for use of minipigs in nonclinical pharmaceutical development: Results of a follow-up IQ DruSafe survey.

Minipigs are valid nonrodent species infrequently utilized for pharmaceutical research and development (R&D) compared with dogs or nonhuman primates (NHPs). A 2022 IQ DruSafe survey revealed a modest increase in minipig use by pharmaceutical companies compared with a prior 2014 survey, primarily in the development of oral small molecules and parenteral protein molecules. Some companies considered using minipigs more often due to NHP shortages and regional ethical concerns with using NHPs and dogs.

Comparison of toxicokinetic parameters of a drug and two metabolites following traditional and capillary microsampling in rat.

Following the request of a regulatory authority, a rat study was conducted to compare pharmacokinetic parameters from traditional large volume sampling and capillary microsampling. Rats were dosed with a proprietary compound in three dose groups and blood samples were collected via capillary microsampling (32 μl), immediately followed by traditional large volume sampling (300 μl) up to 24 h postdose. Resulting plasma samples were analyzed for parent drug and two metabolites.

Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study.

During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation. In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet.

Effect of time and temperature on anticoagulant-dependent pseudothrombocytopenia in Göttingen minipigs.

Background: A marked decrease in thrombocyte count was observed between subsequent measurements of the same EDTA blood sample in several minipigs, but little information was available explaining this finding.

Objectives: The objective was to evaluate the impact of several preanalytic variables on thrombocyte counts in minipigs, in order to improve understanding of the in vitro thrombocyte decrease observed.

Materials And Methods: Hematology blood samples from male and female Göttingen minipigs were collected using EDTA or citrate as an anticoagulant.

The application of capillary microsampling in GLP toxicology studies.

Aim: Capillary microsampling (CMS) to collect microplasma volumes is gradually replacing traditional, larger volume sampling from rats in GLP toxicology studies.

Methodology: About 32 µl of blood is collected with a capillary, processed to plasma and stored in a 10- or 4-µl capillary which is washed out further downstream in the laboratory. CMS has been standardized with respect to materials, assay validation experiments and application for sample analysis.

"All pigs are equal" Does the background data from juvenile Göttingen minipigs support this?

For pediatric indications requiring juvenile toxicity testing, the rat is the preferred species. However, for some drugs it might not be an appropriate model or regulatory agencies may also request a non-rodent species. Due to the relatively recent use of Göttingen minipigs, little background data are available.

Bilateral Symmetrical Idiopathic Necrotizing Encephalopathy: A New Syndrome in Sprague-Dawley Rats.

This article describes the occurrence of a bilaterally symmetrical encephalopathy in Sprague-Dawley rats, which occurred over the period 2005 to 2012 in our laboratory in both untreated control rats and rats treated with different pharmacologically active compounds. The acute brain lesions consisted of degeneration/necrosis in the ventral areas of the brain mostly with little inflammatory response; in the more rare chronic cases there were numerous lipid-laden macrophages. The areas most consistently affected were the crus cerebri, the ventral midbrain, the pyramids, and the internal capsule.

Carcinogenicity in rats of the SGLT2 inhibitor canagliflozin.

The carcinogenicity potential of canagliflozin, an inhibitor of SGLT2, was evaluated in a 2-year rat study (10, 30, and 100 mg/kg). Rats showed an increase in pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors. Systemic exposure multiples at the highest dose relative to the maximum clinical dose were 12- to 21-fold.

Carbohydrate malabsorption mechanism for tumor formation in rats treated with the SGLT2 inhibitor canagliflozin.

Canagliflozin is an SGLT2 inhibitor used for the treatment of type 2 diabetes mellitus. Studies were conducted to investigate the mechanism responsible for renal tubular tumors and pheochromocytomas observed at the high dose in a 2-year carcinogenicity study in rats. At the high dose (100mg/kg) in rats, canagliflozin caused carbohydrate malabsorption evidenced by inhibition of intestinal glucose uptake, decreased intestinal pH and increased urinary calcium excretion.

Gavage-related reflux in rats: identification, pathogenesis, and toxicological implications (review).

After oral gavage dosing of rats, reflux may occur, resulting in serious respiratory effects and mortality. Published information on gavage-related reflux is limited, as it has not yet been a focus of research. Nevertheless, it represents a recurrent challenge in daily toxicology practice of oral gavage dosing.

Unexpected nasal changes in rats related to reflux after gavage dosing.

In a three-week oral gavage toxicity study in rats, a high incidence of respiratory symptoms and high mortality was noted in compound-dosed rats only. Because of audible respiration, an effect in the upper respiratory tract was suspected and the nasal cavity was included for examination. Histology revealed extensive necrosis and purulent inflammation within the nasal passages, indicative of direct irritation.

Quantification and evaluation of antimicrobial drug use in group treatments for fattening pigs in Belgium.

To control the emergence of antimicrobial resistance, knowledge of antimicrobial drug consumption is essential. Because consumption data are not available in Belgium, a study was conducted between March and October 2003 to investigate the antimicrobial drug consumption in pigs, using the treatment incidence based on the animal daily dose pig (ADDpig), the treatment incidence based on the used daily dose pig (UDDpig) (number of ADDpig or UDDpig/1,000 pigs at risk/day), and the ratio UDDpig/ADDpig. The sampling frame consisted of 821 pig herds that (a) used a closed or semi-closed production system, (b) were located in the most dense pig areas of Belgium, and (c) had at least 150 sows and 600 fattening pigs each.

Variability in acquired resistance of Pasteurella and Mannheimia isolates from the nasopharynx of calves, with particular reference to different herd types.

To measure the level of antimicrobial resistance in potential bovine respiratory pathogens at different production types, nasal swabs were collected from 57 calves of 13 dairy herds, 150 calves of 9 beef cattle herds, and 289 calves of 5 high-density veal calf herds and investigated for the presence of Pasteurellaceae. All calves were less than 6 months old. Susceptibilities of the Pasteurella and Mannheimia isolates to eight antimicrobials were determined using an agar dilution method.