Age-related testicular toxicity of mGluR5 negative allosteric modulators appears to be unrelated to testis drug transporter maturity

Campion, Sarah N.; Marcek, John; Kumpf, Steven W.; Chapin, Robert E.; Houle, Christopher; Cappon, Gregg D.

doi:10.1016/j.reprotox.2015.02.001

Cited by 1 publication

(1 citation statement)

References 48 publications

(47 reference statements)

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“…However, some endpoints (eg, developmental milestones) would not be applicable to adults, and other effects, such as on neurobehavioral and reproductive endpoints, have been shown to be highly age-specific and subject to developmental critical periods. [17][18][19][20] The developing nervous and reproductive systems have target processes not seen adults, so extrapolations across age may not be valid for these endpoints. 11,[21][22][23] For example, reproductive toxicity observed in the current survey of juvenile toxicity studies, manifested as changes in mating and fertility, sperm parameters, or reproductive organ histopathology, was not always seen in adults or did not always correspond to the adult effects in terms of type, severity, or reversibility.…”

Section: Discussionmentioning

confidence: 99%

CDER Experience With Juvenile Animal Studies for CNS Drugs

2019

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A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system–active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed. Of the drugs evaluated, all but one had studies conducted in rats. In some cases, a second study in a nonrodent species (dog) was also conducted. Indices of growth and development and standard general toxicity parameters were included in all of the studies. Expanded neurohistopathology evaluations, bone mineral density measurements, and reproductive and neurobehavioral functional assessments were also generally carried out. A variety of neurological and neurobehavioral tests were employed. In the majority of rat studies, the potential for long-term cognitive impairment was evaluated using a complex water maze. Juvenile animal studies provided safety information considered relevant to drug use in children and that was included in labeling for 78% of the applications surveyed. The most commonly reported findings in labeling were for neurobehavioral effects, including changes in locomotor activity, auditory startle habituation, and learning and memory. Of the studies described in labeling with neurobehavioral effects, 54% found these effects to be persistent and to provide evidence of developmental neurotoxicity.

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