Organ data from the developing Göttingen minipig: first steps towards a juvenile PBPK model

Els Van Peer; Noel Downes; Christophe Casteleyn; Chris Van Ginneken; Arie Weeren; Steven Van Cruchten

doi:10.1007/s10928-015-9463-8

Journal of Pharmacokinetics and Pharmacodynamics

April 2016, Volume 43, Issue 2, pp 179–190

Organ data from the developing Göttingen minipig: first steps towards a juvenile PBPK model

Authors
Authors and affiliations

Els Van Peer
Noel Downes
Christophe Casteleyn
Chris Van Ginneken
Arie Weeren
Steven Van CruchtenEmail author

Original Paper

First Online:: 19 December 2015

Received:: 18 August 2015
Accepted:: 05 December 2015

303 Downloads

Abstract

The Göttingen minipig is the most commonly used pig breed in preclinical drug development in Europe and has recently also been explored for physiologically based pharmacokinetic modelling. To develop such a model, not only physiological data from adult animals but also data from juvenile animals are required, especially when using this model for paediatric drug development. Therefore, the aim of our study was to document body and organ weights (brain, heart, lungs, liver, gastrointestinal tract, spleen and kidney), lengths of the small and large intestines and pH values of the gastrointestinal tract in Göttingen minipigs from the foetal stage until the age of 5 months. Postnatal organ and body weights were fitted to regression models to find suitable equations that could be used to estimate organ weights as a function of body weight in the neonatal and juvenile Göttingen minipig. Most organs followed a non-linear growth curve during the first 5 months of life. In general, relative organ weights were the highest during the first week of life, during which the gastric pH was more alkaline than at 28 days of age.

Keywords

Göttingen minipig Growth Organ and body weights Prediction Gastrointestinal pH values

Supplementary material

10928_2015_9463_MOESM1_ESM.xlsx (46 kb)

Supplementary material 1 (XLSX 46 kb)

References

1.
Rostami-Hodjegan A (2012) Physiologically based pharmacokinetics joined with in vitro-in vivo extrapolation of ADME: a marriage under the arch of systems pharmacology. Clin Pharmacol Ther 92(1):50–61. doi:10.1038/clpt.2012.65 CrossRefPubMedGoogle Scholar
2.
Barrett JS, Della Casa Alberighi O, Laer S, Meibohm B (2012) Physiologically based pharmacokinetic (PBPK) modeling in children. Clin Pharmacol Ther 92(1):40–49CrossRefPubMedGoogle Scholar
3.
Suenderhauf C, Parrott N (2013) A physiologically based pharmacokinetic model of the minipig: data compilation and model implementation. Pharm Res 30(1):1–15. doi:10.1007/s11095-012-0911-5 CrossRefPubMedGoogle Scholar
4.
Alcorn J, McNamara PJ (2003) Pharmacokinetics in the newborn. Adv Drug Deliv Rev 55(5):667–686CrossRefPubMedGoogle Scholar
5.
Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med 349(12):1157–1167. doi:10.1056/NEJMra035092 CrossRefPubMedGoogle Scholar
6.
Walthall K, Cappon GD, Hurtt ME, Zoetis T (2005) Postnatal development of the gastrointestinal system: a species comparison. Birth Defects Res B Dev Reprod Toxicol 74(2):132–156. doi:10.1002/bdrb.20040 CrossRefPubMedGoogle Scholar
7.
Casteleyn C, Rekecki A, Van der Aa A, Simoens P, Van den Broeck W (2010) Surface area assessment of the murine intestinal tract as a prerequisite for oral dose translation from mouse to man. Lab Anim 44(3):176–183. doi:10.1258/la.2009.009112 CrossRefPubMedGoogle Scholar
8.
Lin JH, Chiba M, Baillie TA (1999) Is the role of the small intestine in first-pass metabolism overemphasized? Pharmacol Rev 51(2):135–158PubMedGoogle Scholar
9.
Kaminsky LS, Zhang QY (2003) The small intestine as a xenobiotic-metabolizing organ. Drug Metab Dispos 31(12):1520–1525. doi:10.1124/dmd.31.12.1520 CrossRefPubMedGoogle Scholar
10.
Roberts MS, Magnusson BM, Burczynski FJ, Weiss M (2002) Enterohepatic circulation: physiological, pharmacokinetic and clinical implications. Clin Pharmacokinet 41(10):751–790. doi:10.2165/00003088-200241100-00005 CrossRefPubMedGoogle Scholar
11.
Bode G, Clausing P, Gervais F, Loegsted J, Luft J, Nogues V, Sims J (2010) The utility of the minipig as an animal model in regulatory toxicology. J Pharmacol Toxicol Methods 62(3):196–220. doi:10.1016/j.vascn.2010.05.009 CrossRefPubMedGoogle Scholar
12.
Forster R, Bode G, Ellegaard L, van der Laan JW (2010) The RETHINK project on minipigs in the toxicity testing of new medicines and chemicals: conclusions and recommendations. J Pharmacol Toxicol Methods 62(3):236–242. doi:10.1016/j.vascn.2010.05.008 CrossRefPubMedGoogle Scholar
13.
Swindle MM, Makin A, Herron AJ, Clubb FJ Jr, Frazier KS (2012) Swine as models in biomedical research and toxicology testing. Vet Pathol 49(2):344–356. doi:10.1177/0300985811402846 CrossRefPubMedGoogle Scholar
14.
Maharaj AR, Barrett JS, Edginton AN (2013) A workflow example of PBPK modeling to support pediatric research and development: case study with lorazepam. AAPS J 15(2):455–464. doi:10.1208/s12248-013-9451-0 CrossRefPubMedPubMedCentralGoogle Scholar
15.
Maharaj AR, Edginton AN (2014) Physiologically based pharmacokinetic modeling and simulation in pediatric drug development. CPT Pharmacomet Syst Pharmacol 3:e150. doi:10.1038/psp.2014.45 CrossRefGoogle Scholar
16.
Strougo A, Eissing T, Yassen A, Willmann S, Danhof M, Freijer J (2012) First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development. J Pharmacokinet Pharmacodyn 39(2):195–203. doi:10.1007/s10928-012-9241-9 CrossRefPubMedPubMedCentralGoogle Scholar
17.
Ginsberg G, Hattis D, Miller R, Sonawane B (2004) Pediatric pharmacokinetic data: implications for environmental risk assessment for children. Pediatrics 113(4 Suppl):973–983PubMedGoogle Scholar
18.
Van Peer E, Verbueken E, Saad M, Casteleyn C, Van Ginneken C, Van Cruchten S (2014) Ontogeny of CYP3A and p-glycoprotein in the liver and the small intestine of the Gottingen minipig: an immunohistochemical evaluation. Basic Clin Pharmacol Toxicol 114(5):387–394. doi:10.1111/bcpt.12173 CrossRefPubMedGoogle Scholar
19.
Van Peer E, De Bock L, Boussery K, Van Bocxlaer J, Casteleyn C, Van Ginneken C, Van Cruchten S (2015) Age-related differences in CYP3A abundance and activity in the liver of the gottingen minipig. Basic Clin Pharmacol Toxicol. doi:10.1111/bcpt.12410 PubMedGoogle Scholar
20.
Kanerva RL, Alden CL, Wyder WE (1982) The effect of uniform exsanguination on absolute and relative organ weights, and organ weights variation. Toxicol Pathol 10(1):43–44CrossRefGoogle Scholar
21.
Linderkamp O, Berg D, Betke K, Koferl F, Kriegel H, Riegel KP (1980) Blood volume and hematocrit in various organs in newborn piglets. Pediatr Res 14(12):1324–1327. doi:10.1203/00006450-198012000-00010 CrossRefPubMedGoogle Scholar
22.
Cesta MF (2006) Normal structure, function, and histology of the spleen. Toxicol Pathol 34(5):455–465. doi:10.1080/01926230600867743 CrossRefPubMedGoogle Scholar
23.
O’Brien RT, Waller KR 3rd, Osgood TL (2004) Sonographic features of drug-induced splenic congestion. Vet Radiol Ultrasound 45(3):225–227CrossRefPubMedGoogle Scholar
24.
Wilson DV, Evans AT, Carpenter RA, Mullineaux DR (2004) The effect of four anesthetic protocols on splenic size in dogs. Vet Anaesth Analg 31(2):102–108. doi:10.1111/j.1467-2987.2004.00152.x CrossRefPubMedGoogle Scholar
25.
Greenway CV, Stark RD (1969) Vascular responses of the spleen to rapid haemorrhage in the anaesthetized cat. J Physiol 204(1):169–179CrossRefPubMedPubMedCentralGoogle Scholar
26.
Schlesinger AE, Edgar KA, Boxer LA (1993) Volume of the spleen in children as measured on CT scans: normal standards as a function of body weight. AJR Am J Roentgenol 160(5):1107–1109. doi:10.2214/ajr.160.5.8470587 CrossRefPubMedGoogle Scholar
27.
Dekaban AS (1978) Changes in brain weights during the span of human life: relation of brain weights to body heights and body weights. Ann Neurol 4(4):345–356. doi:10.1002/ana.410040410 CrossRefPubMedGoogle Scholar
28.
Voigt J, Pakkenberg H (1983) Brain weight of Danish children. A forensic material. Acta Anat (Basel) 116(4):290–301CrossRefGoogle Scholar
29.
Vujic A, Kosutic J, Bogdanovic R, Prijic S, Milicic B, Igrutinovic Z (2007) Sonographic assessment of normal kidney dimensions in the first year of life–a study of 992 healthy infants. Pediatr Nephrol 22(8):1143–1150. doi:10.1007/s00467-007-0478-2 CrossRefPubMedGoogle Scholar
30.
Johnson TN, Tucker GT, Tanner MS, Rostami-Hodjegan A (2005) Changes in liver volume from birth to adulthood: a meta-analysis. Liver Transplant 11(12):1481–1493. doi:10.1002/lt.20519 CrossRefGoogle Scholar
31.
Noda T, Todani T, Watanabe Y, Yamamoto S (1997) Liver volume in children measured by computed tomography. Pediatr Radiol 27(3):250–252. doi:10.1007/s002470050114 CrossRefPubMedGoogle Scholar
32.
Snoeck V, Cox E, Verdonck F, Joensuu JJ, Goddeeris BM (2004) Influence of porcine intestinal pH and gastric digestion on antigenicity of F4 fimbriae for oral immunisation. Vet Microbiol 98(1):45–53CrossRefPubMedGoogle Scholar
33.
Fallingborg J, Christensen LA, Ingeman-Nielsen M, Jacobsen BA, Abildgaard K, Rasmussen HH, Rasmussen SN (1990) Measurement of gastrointestinal pH and regional transit times in normal children. J Pediatr Gastroenterol Nutr 11(2):211–214CrossRefPubMedGoogle Scholar
34.
Kohn F, Sharifi AR, Simianer H (2007) Modeling the growth of the goettingen minipig. J Anim Sci 85(1):84–92. doi:10.2527/jas.2006-271 CrossRefPubMedGoogle Scholar

Copyright information

Authors and Affiliations

Els Van Peer
- 1
View author's OrcID profile
Noel Downes
- 2
Christophe Casteleyn
- 1
Chris Van Ginneken
- 1
Arie Weeren
- 3
Steven Van Cruchten
- 1
Email author

1.Laboratory of Applied Veterinary Morphology, Department of Veterinary SciencesUniversity of AntwerpWilrijkBelgium
2.Sequani LimitedLedburyUK
3.StatUa Centre for StatisticsUniversity of AntwerpAntwerpBelgium

About this article

CrossMark

Cite this article as:: Van Peer, E., Downes, N., Casteleyn, C. et al. J Pharmacokinet Pharmacodyn (2016) 43: 179. doi:10.1007/s10928-015-9463-8

Organ data from the developing Göttingen minipig: first steps towards a juvenile PBPK model

Abstract

Keywords

Supplementary material

Copyright information

Authors and Affiliations

Personalised recommendations

Cookies