Species Comparison Assays
It is recognized that there is an over-reliance on animal models in preclinical drug discovery and that that the prediction of clinical effects in humans remains poor, in particular with respect to the demonstration of efficacy in humans and the translation from preclinical species. Our ability to perform comparative ex vivo studies across a range of tissue types and disease models, can highlight potential species differences early in the drug development process and provide a bridge between animal and human datasets.
We offer comparative species assays across a wide range of tissue types, including but not limited to respiratory and cardiovascular tissues. Some of our most common comparisons and examples of the similarities and differences between humans and animals are highlighted below.
A review of the literature showing differences in responsiveness of bronchi from various species - no animal model accurately predicts the human response to bronchoconstrictors.
Approximately one-third of all respiratory abnormalities during human clinical trials can be attributed to unforeseen drug-mediated changes in airway resistance. Even guinea pigs, the most commonly used animal model of respiratory function, fail to replicate all human drug responses.
Taken together, these findings suggest that the prediction of human bronchoconstriction could be vastly improved by performing an early species comparison study to explore the relevance of the animal model to humans. At REPROCELL, our scientists can compare the effects of your test compounds on the constriction or relaxation of animal and human airways (bronchi). We can also assess species differences in airway inflammation, using our ex vivo precision-cut lung slice (PCLS) and parenchymal explant models.
|Species||pD2 acetylcholine||pD2 histamine|
|Human||4.56||5.31 ± 0.27|
|Guinea pig||5.89||5.31 ± 0.72|
Many drugs have been shown to have a direct effect on cardiac function, but cardiac safety data generated in animals do not always mimic the human drug response. Our scientists can provide species comparison assays to determine whether your cardiac safety data will translate to humans. Several of our clients have used these studies to troubleshoot clinical adverse effects. For example, Amgen compared the vasodilation effects of their test article in canine and human blood vessels after clinical trial participants started experiencing headaches. They found that the drug caused significant vasodilation ex vivo, which they were able to reverse using an adenosine receptor agonist.
The 5-HT (serotonin) pathway is more prominent in the coronary artery function of humans than in canine tissues.
Our scientists can provide studies in human and rat uterine tissue to identify species differences in uterine contractility. The graph below shows that the response of these tissues to oxytocin is markedly different, meaning animal tests measuring uterine contractility may not fully reflect the human response.
Cumulative concentration-response curve to oxytocin in human and rat isolated uterine muscle strips (n=3). A: Human results show the change in peak frequency as a percentage of baseline peak frequency in response to oxytocin exposure B: Rat results show the change in baseline expressed as a percentage of baseline in response to oxytocin exposure.
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