Maternal Stress Affects Fetal Growth but Not Developmental Instability in Rabbits

Developmental instability (DI), often measured by fluctuating asymmetry (FA) or the frequency of phenodeviants (fPD), is thought to increase with stress. However, specifically for stressors of maternal origin, evidence of such negative associations with DI is scarce. Whereas effects of maternal stress on DI have predominately been examined retroactively in humans, very little is known from experiments with well-defined stress levels in animal model systems. The aim of this study was to examine the effects of maternal exposure to three doses (plus a control) of a toxic compound affecting maternal condition on DI of their offspring in rabbits. Presence of maternal stress induced by the treatment was confirmed by a decrease in food consumption and weight gain of gravid females in the medium and high dose. Major abnormalities and mortality were unaffected by dose, suggesting the lack of toxic effects of the compound on the offspring. In spite of string maternal stress, offspring FA did not increase with dose. The treatment did lead to elevated fPD, but most were transient, reflecting growth retardation. Furthermore, a consistent association between fPD and FA was absent. These findings indicate that DI is not increased by maternal stress in this animal model

In vivo longitudinal micro-CT study of bent long limb bones in rat offspring

A

Non-clinical safety considerations for development of medicines targeted primarily at pediatric use: An industry view

This paper provides considerations on approaches to the development of medicines targeted primarily for pediatric use. Drugs initially developed for pediatric use, i.e. ‘pediatric-first’ or ‘pediatric-only’ drugs, indicate pediatric drugs with no adult indication and may use first-in-human studies in adult or pediatric populations. These terms should not be confused with the definition ‘first-in-pediatrics’, i.e. when a drug is given first time to a pediatric population, irrespective of whether the drug has an adult indication in addition to a pediatric indication. The most common development approach to pediatric-first drugs involves a first in human (FIH) clinical trial with healthy adult volunteers to assess safety and tolerability in accordance with relevant regulatory guidelines (add ref). This approach generally requires traditional non-clinical repeat-dose studies in adult rodent and non-rodent species (reference to ICH M3(R2) ?). Safety pharmacology and genetic toxicology studies in adult animals are also performed for small molecule drugs. Additional studies in juvenile (i.e. immature) animals may be required prior to clinical trials in pediatric patients, on a case-by-case basis guided by knowledge of the pharmacological target, existing data in adult animals and humans, and risk-benefit considerations. In this paradigm the starting dose for pediatric patients is primarily driven by modeling from the adult PK assessment and pharmacology data. A second development approach is where the FIH clinical trial is conducted in pediatric patients (e.g. when involving healthy adult volunteers would be ethically unacceptable), with the option of a deferral for the younger age categories. This approach is generally supported by repeat-dose studies in juvenile rodent and non-rodent species, with the onset of dosing at ages that developmentally correlate to the age of the pediatric patients. The safety pharmacology and in vivo genetic toxicology studies are still, however, generally performed in adult animals for small molecule drugs. To define a safe yet minimally efficacious starting dose for pediatric patients, various complementing approaches can be used, including human equivalent dose, minimal anticipated biological effect level, and physiologically based pharmacokinetic modeling. Similar considerations apply to the development of biopharmaceuticals, with the caveat that often non-human primates are the only relevant species, in which case safety pharmacology endpoints are often included in the repeat-dose studies and genetic toxicology are usually not required. Because the non-clinical development strategy is driven by the clinical requirements, timely interactions with regulatory authorities are recommended to address key clinical questions early on, such as age groups, dosing regimen, and currently available therapies. Case examples for pediatric-first drug candidates show how both drug development approaches, i.e. entry into human first in adults or directly in pediatric populations are used in the pharmaceutical industry

MRI Imaging of Liver Fibrosis with Vitamin A Functionalized Magnetolipossomes in Rats

Garcia Ribeiro R.S., Van Santvoort A., Kektar-Atre A., de Schaepdrijver L., Bueters R., Rangarajan J.R., van Heerden M., Himmelreich U., ''MRI imaging of liver fibrosis with vitamin A functionalized magnetolipossomes in rats'', 2nd Belgian molecular imaging congress - BMIC 2015, April 22, 2015, Brussels, Belgium.status: publishe

The benefits, limitations and opportunities of preclinical models for neonatal drug development

Increased research to improve preclinical models to inform the development of therapeutics for neonatal diseases is an area of great need. This article reviews five common neonatal diseases – bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, perinatal hypoxic–ischemic encephalopathy and neonatal sepsis – and the available in vivo, in vitro and in silico preclinical models for studying these diseases. Better understanding of the strengths and weaknesses of specialized neonatal disease models will help to improve their utility, may add to the understanding of the mode of action and efficacy of a therapeutic, and/or may improve the understanding of the disease pathology to aid in identification of new therapeutic targets. Although the diseases covered in this article are diverse and require specific approaches, several high-level, overarching key lessons can be learned by evaluating the strengths, weaknesses and gaps in the available models. This Review is intended to help guide current and future researchers toward successful development of therapeutics in these areas of high unmet medical need

Micro-CT Imaging: Developing criteria for examining fetal skeletons in regulatory developmental toxicology studies - A Workshop Report

During the past two decades the use and refinements of imaging modalities have markedly increased making it possible to image embryos and fetuses used in pivotal nonclinical studies submitted to regulatory agencies. Implementing these technologies into the Good Laboratory Practice environment requires rigorous testing, validation and documentation to ensure the reproducibility of data. A workshop on current practices and regulatory requirements was held with the goal of defining minimal criteria for the proper implementation of these technologies and subsequent submission to regulatory agencies. Micro-computed tomography (micro-CT) is especially well suited for high-throughput evaluations, and is gaining popularity to evaluate fetal skeletons to assess the potential developmental toxicity of test agents. This workshop was convened to help scientists in the developmental toxicology field understand and apply micro-CT technology to nonclinical toxicology studies and facilitate the regulatory acceptance of imaging data. Presentations and workshop discussions covered: (1) principles of micro-CT fetal imaging; (2) concordance of findings with conventionally stained specimens; and (3) regulatory requirements for validating the system. Establishing these requirements for micro-CT examination can provide a path forward for laboratories considering implementing this technology and provide regulatory agencies with a basis to consider the acceptability of data generated via this technology

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals : on systemic dose and developmental effects

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (Cmax) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and Cmax exposures. For 13.5% of the compounds the rabbit was more sensitive and for 3.5% of compounds the rat was more sensitive when compared based on AUC exposures. For 12% of the compounds the rabbit was more sensitive and for 1.3% of compounds the rat was more sensitive based on Cmax exposures. When evaluated based on human equivalent dose (HED) conversion using standard factors, the rat and rabbit were equally sensitive. The relative extent of embryo-fetal toxicity in the presence of maternal toxicity was not different between species. Overall effect severity incidences were distributed similarly in rat and rabbit studies. Individual rat and rabbit strains did not show a different general distribution of systemic exposure LOAELs as compared to all strains combined for each species. There were no apparent species differences in the occurrence of embryo-fetal variations. Based on power of detection and given differences in the nature of developmental effects between rat and rabbit study outcomes for individual compounds, EFDT studies in two species have added value over single studies