The utility of the minipig as an animal model in regulatory toxicology

Bode, Gerd; Clausing, Peter; Gervais, Frédéríc; Loegsted, Jeanet; Luft, Jörg; Nogués, Vicente; Sims, Jennifer

doi:10.1016/j.vascn.2010.05.009

Cited by 352 publications

(276 citation statements)

References 134 publications

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“…Yucatan minipigs have been reported to reach sexual and skeletal maturity at the age of 7 to 10 months [52] and 26 to 30 months [9,34], respectively. These animals had undergone surgery on the left knee, for which the biomechanical data were reported [39].…”

Section: Methodsmentioning

confidence: 99%

Validation of Porcine Knee as a Sex-specific Model to Study Human Anterior Cruciate Ligament Disorders

Kiapour

Shalvoy

Murray

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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Background Animal models have long been considered an important modality for studying ACL injuries. However, to our knowledge, the value of these preclinical models to study sex-related phenomena associated with ACL injury and recovery has not been evaluated. Questions/purposesWe asked whether (1) prominent anatomic and (2) biomechanical factors differ between female and male porcine knees, particularly those known to increase the risk of ACL injury. Methods Eighteen intact minipig knees (nine males, nine females) underwent MRI to determine the femoral bicondylar width, intercondylar notch size (width, area and index), medial and lateral tibial slope, ACL size (length, cross-sectional area, and volume), and medial compartment tibiofemoral cartilage thickness. AP knee laxity at 30°, 60°, and 90°flexion and ACL tensile structural properties were measured using custom-designed loading fixtures in a universal tensile testing apparatus. Comparisons between males and females were performed for all anatomic and biomechanical measures. The findings then were compared with published data from human knees. Results Female pigs had smaller bicondylar widths (2.9 mm, ratio = 0.93, effect size = À1.5) and intercondylar notches (width: 2.0 mm, ratio = 0.79, effect size = À2.8; area: 30.8 mm 2 , ratio = 0.76, effect size = 2.1; index: 0.4, ratio = 0.84, effect size = À2.0), steeper lateral tibial slope (4.3°, ratio = 1.13, effect size = 1.1), smaller ACL (length: 2.7 mm, ratio = 0.91, effect size = 1.1; area: 6.8 mm 2 , ratio = 0.74, effect size = À1.5; volume: 266.2 mm 3 , ratio = 0.68, effect size = À1.5), thinner medial femoral cartilage (0.4 mm, ratio = 0.8, effect size = À1.1), lower ACL yield load (275 N, ratio = 0.81, effect size = À1.1), and greater AP knee laxity at 30°( 0.7 mm, ratio = 1.32, effect size = 1.1) and 90°(0.5 mm, ratio = 1.24, effect size = 1

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Section: Methodsmentioning

confidence: 99%

Validation of Porcine Knee as a Sex-specific Model to Study Human Anterior Cruciate Ligament Disorders

Kiapour

Shalvoy

Murray

et al. 2015

Clinical Orthopaedics &Amp; Related Research

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“…Currently, the minipig is considered a useful alternative nonrodent species for safety evaluation of (bio)pharmaceuticals (Bode et al, 2010;Forster et al, 2010a, b). Minipigs have been shown to be suitable and are recognized and accepted by regulatory authorities worldwide (van der Laan et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Minipigs have been shown to be suitable and are recognized and accepted by regulatory authorities worldwide (van der Laan et al, 2010). Although the role for minipigs in safety testing of pharmaceuticals, food additives, and agrochemicals is increasing, there is still a significant gap in knowledge concerning the utility of the minipig for biologics/biotechnology products (Bode et al, 2010). The potential use of minipigs for immunotoxicity (including immunogenicity) testing and immunopharmacology testing of biopharmaceuticals in order to further evaluate their predictive value for human safety still needs more attention.…”

Section: Introductionmentioning

confidence: 99%

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Mierlo

Cnubben

Wouters

et al. 2013

Journal of Immunotoxicology

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Immunogenicity is a major issue of concern for monoclonal antibodies used in human diseases and is by default mainly determined in non-human primates (NHP), as target molecules are considered most similar in NHP compared to human. In this manuscript the predictive value of immunogenicity testing in minipigs for human safety is evaluated, as the immune system of the pig is functionally similar to that in other mammalian species. Adalimumab and infliximab (both monoclonal antibodies blocking TNFa) were used as model substances. Female Gö ttingen minipigs (4/group) were treated every other week with low (0.1 mg/kg), mid (1.0 mg/kg), or high dose (5 mg/kg) adalimumab or 5 mg/kg infliximab subcutaneous (SC) over a period of 8 weeks. After first and last dosing, pharmacokinetic analysis was performed. Anti-drug antibodies (ADAs) were measured on several time points. Furthermore, hematology, clinical chemistry, body weight, clinical signs, and histopathology of several organs were evaluated. No signs of toxicity of the treatments were observed in the limited organs and tissues collected. Eleven out of 12 minipigs treated with adalimumab elicited a detectable ADA response. Induction of ADA was correlated with decreased plasma levels of adalimumab. Infliximab clearance was comparable after first and last dose. Therefore, the presence of ADA directed to infliximab was considered highly unlikely. It was concluded that the minipig and NHP showed comparable suitability for immunogenicity prediction in humans. More studies with other biopharmaceutical products are needed to strengthen the status of the minipig as an alternative model for immunotoxicity testing including immunogenicity.

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“…To obtain valuable information on pharmacological and toxicological effects of a drug candidate for subsequent clinical development in man, the commonly used species (mice, rats, rabbits, and dogs) may not always be appropriate. The minipig could be a good alternative as its anatomy and physiology are very similar to those of humans in many aspects (Jørgensen 1998;Bode et al 2010;McAnulty et al 2012). In regulatory toxicology studies, female Göttingen minipigs are typically 4-5 months of age at the start of experimental studies.…”

mentioning

confidence: 99%

“…In regulatory toxicology studies, female Göttingen minipigs are typically 4-5 months of age at the start of experimental studies. At this age, they are expected to be sexually mature based on breeding experience (Jørgensen 1998;Bode et al 2010;Creasy 2012). However, experimental data on the onset of sexual maturation in female Göttingen minipigs are lacking in the literature and are required for a reliable evaluation of reproductive functioning.…”

mentioning

confidence: 99%

Sexual Maturation in the Female Göttingen Minipig

Peter¹,

Rijk²,

Zeltner³

et al. 2016

Toxicol Pathol

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In the literature, experimental data on sexual maturation of female Gö ttingen minipigs are lacking. This may impede a reliable evaluation of reproductive functioning, particularly in the young (immature) sow used in toxicity studies. To find suitable method(s) to detect ovulation during in-life, a pilot study was performed with 3 adult sows (approximately 10-11 months), followed by a study with 14 immature females (approximately 3-4 months). From the tested parameters, progesterone analysis was the most reliable predictor. First progesterone peaks were observed in 13 sows at 3.7-4.2 or 5.5-6.5 months with a cycle length of 17-22 days. One sow did not show progesterone release until necropsy at 7 months of age. Histopathology of the reproductive organs confirmed sexual maturity for all sows, except the one without progesterone peak. In conclusion, the age range of sexual maturity of female Gö ttingen minipigs (3.7-6.5 months) is much wider than previously thought, and in-life progesterone analysis is a useful tool to determine sexual maturity of individual animals.

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The utility of the minipig as an animal model in regulatory toxicology

Cited by 352 publications

References 134 publications

Validation of Porcine Knee as a Sex-specific Model to Study Human Anterior Cruciate Ligament Disorders

Validation of Porcine Knee as a Sex-specific Model to Study Human Anterior Cruciate Ligament Disorders

The minipig as an alternative non-rodent model for immunogenicity testing using the TNFα blockers adalimumab and infliximab

Sexual Maturation in the Female Göttingen Minipig

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