Juvenile Animal Testing: Assessing Need and Use in the Drug Product Label

Baldrick, Paul

doi:10.1177/2168479017750129

Cited by 10 publications

(4 citation statements)

References 12 publications

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“…In a recent survey on European Pediatric Investigation Plan (PIP) decisions (2007-2017, 229 drugs) with juvenile animal requests, general toxicological studies were the most applicable study designs, with infectious diseases, endocrinology, neurology and cardiovascular diseases being the most common therapeutic areas. As anticipated, about 80% of these studies were in rats, while studies in pigs were limited (4.2%) [22]. Interestingly, a recent European Medicines Agency (EMA) analysis on juvenile animal studies in the field of anticancer drug research documented that juvenile models also generated evidence regarding new target organ toxicity (kidney, central and peripheral nervous system, impaired learning or memory, cardiac system) or increased severity of toxicity (including mortality rate) [23].…”

Section: Introductionmentioning

confidence: 78%

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development

et al. 2020

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Pharmacotherapy in pediatric patients is challenging in view of the maturation of organ systems and processes that affect pharmacokinetics and pharmacodynamics. Especially for the youngest age groups and for pediatric-only indications, neonatal and juvenile animal models can be useful to assess drug safety and to better understand the mechanisms of diseases or conditions. In this respect, the use of neonatal and juvenile pigs in the field of pediatric drug discovery and development is promising, although still limited at this point. This review summarizes the comparative postnatal development of pigs and humans and discusses the advantages of the juvenile pig in view of developmental pharmacology, pediatric diseases, drug discovery and drug safety testing. Furthermore, limitations and unexplored aspects of this large animal model are covered. At this point in time, the potential of the neonatal and juvenile pig as nonclinical safety models for pediatric drug development is underexplored.

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Section: Introductionmentioning

confidence: 78%

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development

et al. 2020

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“…The current selection of toxicology animal models usually includes time of physiological development and organ development similar to humans, costs, and ease of obtaining experimental animals [ 32 ]. In this study, we selected SD rats for the safety investigation.…”

Section: Discussionmentioning

confidence: 99%

Study on the Safety of Human Oligodendrocyte Precursor Cell Transplantation in Young Animals and Its Efficacy on Myelination

Zhou

et al. 2021

Stem Cells and Development

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Oligodendrocyte precursor cells (OPCs), which can differentiate into myelinating oligodendrocytes during embryonic development, are an important potential source for myelin repair or regeneration. To date, OPCs from human sources (hOPCs) remain limited. In this study, we aimed to evaluate the safety and remyelination capacity of hOPCs developed in our laboratory by transplanting them into the lateral ventricles of Sprague-Dawley rats of different ages. The toxicity, biodistribution, and tumor formation abilities of the injected hOPCs were examined by evaluating rats' vital signs, developmental indicators, neural re exes, along with hematological, immunological, and pathological assessments. In addition, the hOPCs were transplanted into the corpus callosum of shiverer mice to verify cell myelination e cacy.Overall, our results showed that transplanted hOPCs into young mice showed no toxicity against their organ function or immune system, engrafted only in the brain, and caused no tissue proliferation or tumor formation. In terms of e cacy, the transplanted hOPCs formed myelin in the corpus callosum, alleviated the trembling phenotype of shiverer mice, and promoted normal development. The transplantation of hOPCs is safe and can effectively form myelin in the brain, thereby providing a theoretical basis for the future clinical transplantation of hOPCs.

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“…The use of juvenile animal models might bridge that gap. Despite the increase in juvenile animal trials thanks to the pediatric legislations, almost all juvenile studies mentioned in the PIPs from 2007 to mid-2017 were general toxicology studies (Baldrick, 2018). Besides toxicology studies, there is a need for more pharmacokinetic (PK) and pharmacodynamic (PD) juvenile studies in the desired age category without any previous adult human or animal data.…”

Section: Introductionmentioning

confidence: 99%

“…Selecting the most appropriate animal species is crucial and the rat (57.5%) is still the most commonly used juvenile species, followed by dog (8%), mouse (4.5%), monkey (4%), pig (2%), sheep (1%), rabbit (1%), and hamster (0.5%). Unfortunately, in 21.5% of the cases, no species was mentioned (Baldrick, 2018). However, this does not mean that the rat is the most appropriate animal model to evaluate pediatric PK/PD and safety characteristics.…”

Section: Introductionmentioning

confidence: 99%

Developmental Pharmacokinetics and Safety of Ibuprofen and Its Enantiomers in the Conventional Pig as Potential Pediatric Animal Model

et al. 2019

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Pediatric drug development, especially in disease areas that only affect children, can be stimulated by using juvenile animal models not only for general safety studies, but also to gain knowledge on the pharmacokinetic and pharmacodynamic properties of the drug. Recently, the conventional growing piglet has been suggested as juvenile animal model. However, more studies with different classes of drugs are warranted to make a thorough evaluation whether the juvenile pig might be a suitable preclinical animal model. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory drugs in human. The present study determined the PK parameters, gastro-intestinal and renal safety of 5 mg/kg BW ibuprofen after single intravenous, single oral and multiple oral administration to each time eight pigs (four males, four females) aging 1, 4, 8 weeks and 6–7 months. Oral administration was performed via a gastrostomy button. A jugular catheter was used for intravenous administration and blood sampling. To assess NSAID induced renal toxicity, renal function was evaluated using iohexol and p -aminohippuric acid as markers for glomerular filtration rate and renal plasma flow, respectively. After the trial, necropsy and histology was performed to evaluate macroscopic and microscopic gastro-intestinal as well as renal lesions. Both enantiomers, R-ibuprofen and S-ibuprofen, were determined in plasma using an in-house developed and validated UHPLC-MS/MS method. Pharmacokinetic parameters were estimated using compartmental analysis. Clearance and volume of distribution of total ibuprofen and both enantiomers increased with age as was observed in human. The rate of stereochemical conversion decreased with age. Multiple oral dosing decreased the absolute oral bioavailability and maximum plasma concentration of R-ibuprofen and food consumption did not influence drug absorption. Based on the limited available pediatric literature, the current study might suggest the conventional pig as suitable animal model to evaluate NSAIDs for pediatric use.

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Juvenile Animal Testing: Assessing Need and Use in the Drug Product Label

Cited by 10 publications

References 12 publications

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development

The Neonatal and Juvenile Pig in Pediatric Drug Discovery and Development

Study on the Safety of Human Oligodendrocyte Precursor Cell Transplantation in Young Animals and Its Efficacy on Myelination

Developmental Pharmacokinetics and Safety of Ibuprofen and Its Enantiomers in the Conventional Pig as Potential Pediatric Animal Model

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