Haematology and biochemistry changes related to age in Göttingen minipigs
1
S180 Abstracts / Toxicology Letters 211S (2012) S43–S216 including studies by subcutaneous route. All available information was assessed using a dedicated decision tree based on a weight of evidence approach. Depending on the quality of data and the degree of discrepancy between studies, each type of effect was qualified in terms of recognized, suspected, controversial or as no conclu- sive effects. The available data were presented by their windows of exposure (pre natal, peri-natal). Results. Some effects were consid- ered as recognised in animals, including: effects on neurogenesis after pre or peri-natal exposure; effects on lipogenesis after pre- or peri- natal exposure or exposure in adulthood; development of intraductal hyperplastic lesions after pre- or perinatal exposure and acceleration of architectural maturation of the mammary glands in adulthood. Based on the limited human data, metabolism and car- diovascular diseases were considered as suspected while the effects on brain behaviour and on breast were not conclusive. Conclusions. Further to this analysis, recognised effects in animals and suspected effects in humans will be used for the risk assessment procedure, taking into account all routes of exposure to BPA. doi:10.1016/j.toxlet.2012.03.647 P29-13 Vehicles & excipients used in minipigs—Review of use in marketed drug products Niels-Christian Ganderup Ellegaard Göttingen Minipigs, Denmark Selection of suitable vehicles and/or excipients is critical in both non-clinical and clinical studies as formulation impacts the intrin- sic characteristics of the final drug product, e.g., (extended) release, absorption, distribution and (local) tolerance, to mention some. Inappropriate selection of vehicles and/or excipients can have neg- ative impact on drug evaluation (which may be unwarranted) and consequently delay or stop development. This type of information is available for mice, rats, rabbits, dogs and non-human primates (NHP), but information specific to minipigs is scarce. More than forty marketed drug products (FDA/EMA dossiers) have been reviewed and vehicles and excipients used are presented in this poster. Data includes information on route of administration, dosage, study duration, and (where possible) notable reactions. Published literature on this topic is also included. This provides the non-clinical experimenter with a valuable tool in his or her work. doi:10.1016/j.toxlet.2012.03.648 P29-14 Review of marketed drugs supported by the minipig as non-rodent species Niels-Christian Ganderup Ellegaard Göttingen Minipigs, Democratic People’s Republic of Korea Minipigs, like conventional pigs, are used as models of human disease and in safety studies of new medicines, medical devices, food additives and pesticides. This poster reviews the historical use of the minipig as a non-rodent species in regulatory toxicity testing to support new medicines and presents data on routes of adminis- tration, clinical indications as well as mechanism of action (where if possible) for more than forty marketed drug products. It also includes a qualitative assessment of the predictive value of the minipig by comparing adverse reactions in clinical trials and minipig studies. The most readily available source of comprehen- sive and unbiased information about licensed drugs is found in the publicly available databases of major regulatory agencies, where there are extensive non-clinical and clinical data from company submissions and it is critical assessment by independent experts. For the present analysis searches were made of two princi- pal databases covering medicines registered in the USA, namely Drugs@FDA, and in the European Community EMA European Pub- lic Assess-ment Reports (EPARs); data mining and searches of said databases was done using PharmaPendium ® . Such informa- tion pertaining to minipigs has, to the authors knowledge, never been published before, and is therefore seen as both new and ground breaking and surely warrants rethinking of the potential this species holds as non-rodent species in safety assessment. doi:10.1016/j.toxlet.2012.03.649 P29-15 Haematology and biochemistry changes related to age in Göttingen minipigs Andrew Makin, Jes T. Jensen, Signe Klastrup CiToxLAB, Denmark Minipigs are commonly used non-rodents in toxicology studies. We use Göttingen minipigs at a range of ages and developmental stages from neonatal up to around two years of age depending on the type of study. Minipigs develop rapidly. They are born with open eyes and can walk. They wean at 4 weeks and are sexually mature at 4 to 6 months. Despite maturing early, they continue to grow during the first 2 years of their lives. Therefore an animal at the end of a chronic toxicity study is significantly bigger and more developed than at the start. This is reflected by other changes than just increased size. Findings in toxicology studies must be put into context using both concurrent control and historical data. We were interested to see how some routine parameters measured in toxicology studies change over time. There will always be results that need a deeper explanation, which is where the background data is of value. In our poster, we present a significant amount of control data from minipigs covering a range of ages, highlighting changes that could be expected to be seen over time. Our data indicates that values for certain parameters, e.g. red blood cells, change significantly over short times, especially in younger animals. However, values for other parameters (e.g. serum protein and creatinine) continue to change with age even in mature animals. These results demonstrate that a database of age-matched results is invaluable in supporting interpretation of findings in tox- icology studies in the minipig. doi:10.1016/j.toxlet.2012.03.650 P29-16 Reducing dog use in one month toxicology studies without affecting scientific quality Sally Robinson 1 , Kristian Konigsson 2 , Hans Harlemann 1 1 United Kingdom, 2 AstraZeneca, Sweden Assessing reversibility of treatment related changes is impor- tant in risk assessment and embodied in regulatory guidance. Within AstraZeneca reversibility is incorporated into the one month toxicology studies.
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Transcript of Haematology and biochemistry changes related to age in Göttingen minipigs
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180 Abstracts / Toxicology L
ncluding studies by subcutaneous route. All available informationas assessed using a dedicated decision tree based on a weight of
vidence approach. Depending on the quality of data and the degreef discrepancy between studies, each type of effect was qualifiedn terms of recognized, suspected, controversial or as no conclu-ive effects. The available data were presented by their windows ofxposure (pre natal, peri-natal). Results. Some effects were consid-red as recognised in animals, including: effects on neurogenesisfter pre or peri-natal exposure; effects on lipogenesis after pre-r peri- natal exposure or exposure in adulthood; development ofntraductal hyperplastic lesions after pre- or perinatal exposure andcceleration of architectural maturation of the mammary glands indulthood. Based on the limited human data, metabolism and car-iovascular diseases were considered as suspected while the effectsn brain behaviour and on breast were not conclusive. Conclusions.urther to this analysis, recognised effects in animals and suspectedffects in humans will be used for the risk assessment procedure,aking into account all routes of exposure to BPA.
oi:10.1016/j.toxlet.2012.03.647
29-13ehicles & excipients used in minipigs—Review of use inarketed drug products
iels-Christian Ganderup
Ellegaard Göttingen Minipigs, Denmark
Selection of suitable vehicles and/or excipients is critical in bothon-clinical and clinical studies as formulation impacts the intrin-ic characteristics of the final drug product, e.g., (extended) release,bsorption, distribution and (local) tolerance, to mention some.nappropriate selection of vehicles and/or excipients can have neg-tive impact on drug evaluation (which may be unwarranted) andonsequently delay or stop development. This type of informations available for mice, rats, rabbits, dogs and non-human primatesNHP), but information specific to minipigs is scarce.
More than forty marketed drug products (FDA/EMA dossiers)ave been reviewed and vehicles and excipients used are presented
n this poster. Data includes information on route of administration,osage, study duration, and (where possible) notable reactions.ublished literature on this topic is also included. This provides theon-clinical experimenter with a valuable tool in his or her work.
oi:10.1016/j.toxlet.2012.03.648
29-14eview of marketed drugs supported by the minipig ason-rodent species
iels-Christian Ganderup
Ellegaard Göttingen Minipigs, Democratic People’s Republic of Korea
Minipigs, like conventional pigs, are used as models of humanisease and in safety studies of new medicines, medical devices,ood additives and pesticides. This poster reviews the historical usef the minipig as a non-rodent species in regulatory toxicity testingo support new medicines and presents data on routes of adminis-ration, clinical indications as well as mechanism of action (where
f possible) for more than forty marketed drug products.It also includes a qualitative assessment of the predictive valuef the minipig by comparing adverse reactions in clinical trials andinipig studies. The most readily available source of comprehen-
211S (2012) S43–S216
sive and unbiased information about licensed drugs is found in thepublicly available databases of major regulatory agencies, wherethere are extensive non-clinical and clinical data from companysubmissions and it is critical assessment by independent experts.
For the present analysis searches were made of two princi-pal databases covering medicines registered in the USA, namelyDrugs@FDA, and in the European Community EMA European Pub-lic Assess-ment Reports (EPARs); data mining and searches ofsaid databases was done using PharmaPendium®. Such informa-tion pertaining to minipigs has, to the authors knowledge, neverbeen published before, and is therefore seen as both new andground breaking and surely warrants rethinking of the potentialthis species holds as non-rodent species in safety assessment.
doi:10.1016/j.toxlet.2012.03.649
P29-15Haematology and biochemistry changes related to age inGöttingen minipigs
Andrew Makin, Jes T. Jensen, Signe Klastrup
CiToxLAB, Denmark
Minipigs are commonly used non-rodents in toxicology studies.We use Göttingen minipigs at a range of ages and developmentalstages from neonatal up to around two years of age depending onthe type of study. Minipigs develop rapidly. They are born withopen eyes and can walk. They wean at 4 weeks and are sexuallymature at 4 to 6 months. Despite maturing early, they continue togrow during the first 2 years of their lives. Therefore an animal atthe end of a chronic toxicity study is significantly bigger and moredeveloped than at the start. This is reflected by other changes thanjust increased size.
Findings in toxicology studies must be put into context usingboth concurrent control and historical data. We were interested tosee how some routine parameters measured in toxicology studieschange over time. There will always be results that need a deeperexplanation, which is where the background data is of value. Inour poster, we present a significant amount of control data fromminipigs covering a range of ages, highlighting changes that couldbe expected to be seen over time.
Our data indicates that values for certain parameters, e.g. redblood cells, change significantly over short times, especially inyounger animals. However, values for other parameters (e.g. serumprotein and creatinine) continue to change with age even in matureanimals. These results demonstrate that a database of age-matchedresults is invaluable in supporting interpretation of findings in tox-icology studies in the minipig.
doi:10.1016/j.toxlet.2012.03.650
P29-16Reducing dog use in one month toxicology studies withoutaffecting scientific quality
Sally Robinson 1, Kristian Konigsson 2, Hans Harlemann 1
1 United Kingdom, 2 AstraZeneca, Sweden
Assessing reversibility of treatment related changes is impor-
tant in risk assessment and embodied in regulatory guidance.Within AstraZeneca reversibility is incorporated into the onemonth toxicology studies.
