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Predicting Human Drug Toxicity and Safety via Animal Tests: Can Any One Species Predict Drug Toxicity in Any Other, and Do Monkeys Help?

Jarrod Bailey, Michelle Thew and Michael Balls

Animals are still widely used in drug development and safety tests, despite evidence for their lack of predictive value. In this regard, we recently showed, by producing Likelihood Ratios (LRs) for an extensive data set of over 3,000 drugs with both animal and human data, that the absence of toxicity in animals provides little or virtually no evidential weight that adverse drug reactions will also be absent in humans. While our analyses suggest that the presence of toxicity in one species may sometimes add evidential weight for risk of toxicity in another, the LRs are extremely inconsistent, varying substantially for different classes of drugs. Here, we present further data from analyses of other species pairs, including nonhuman primates (NHPs), which support our previous conclusions, and also show in particular that test results inferring an absence of toxicity in one species provide no evidential weight with regard to toxicity in any other species, even when data from NHPs and humans are compared. Our results for species including humans, NHPs, dogs, mice, rabbits, and rats, have major implications for the value of animal tests in predicting human toxicity, and demand that human-focused alternative methods are adopted in their place as a matter of urgency.
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An Analysis of the Use of Animal Models in Predicting Human Toxicology and Drug Safety

Jarrod Bailey, Michelle Thew and Michael Balls

Animal use continues to be central to preclinical drug development, in spite of a lack of its demonstrable validity. The current nadir of new drug approvals and the drying-up of pipelines may be a direct consequence of this. To estimate the evidential weight given by animal data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive data set of 2,366 drugs, for which both animal and human data are available, including tissue-level effects and MedDRA Level 1–4 biomedical observations. This was done for three preclinical species (rat, mouse and rabbit), to augment our previously-published analysis of canine data. In common with our dog analysis, the resulting LRs show: a) that the absence of toxicity in the animal provides little or virtually no evidential weight that adverse drug reactions (ADRs) will also be absent in humans; and b) that, while the presence of toxicity in these species can add considerable evidential weight for human risk, the LRs are extremely inconsistent, varying by over two orders of magnitude for different classes of compounds and their effects. Therefore, our results for these additional preclinical species have important implications for their use in predicting human toxicity, and suggest that alternative methods are urgently required.

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Description of a Dynamic In Vitro Model of the Dog Gastrointestinal Tract and an Evaluation of Various Transit Times for Protein and Calcium

Marianne J.E. Smeets-Peeters, Mans Minekus, Robert Havenaar, Gertjan Schaafsma and Martin W.A. Verstegen

In order to manufacture complete and balanced dog diets, it is important to know the nutrient requirements of dogs and the availability of these nutrients from food. As pet food manufacturers are restricted in their options for (invasive) animal studies, due to ethical constraints, it is important to have alternative methods for researching the effects of various dog diets. To simulate the gastrointestinal tract of the dog, the dynamic gastrointestinal tract model developed by Minekus et al. was further developed and modified in this study. The model consists of four compartments which simulate the stomach and small intestine (duodenum, jejunum and ileum). Each compartment is made of glass, with a flexible inner wall. This wall can be compressed by increasing the pressure of the surrounding water, mimicking the peristaltic movements and mixing seen in vivo. The model is computer-controlled to simulate physiological parameters such as pH, transit time and secretion of digestive juices, as derived from the literature. Gastric meal delivery and the effects of intestinal transit time on protein digestibility and availability for absorption of calcium from dog food were studied to evaluate the model. The gastric meal delivery of dry dog food was identical to a preset curve, which was based on in vivo data from healthy dogs. The emptying time for canned dog food was somewhat slower than the preset values, probably due to the viscosity of the meal. The differences between the preset values and the measured delivery were not significant. The digestibility of protein and the availability of calcium for absorption increased with a longer transit time. A significant difference was found between medium and slow transit times for the nitrogen content in the ileal delivery effluent and the jejunal dialysates (p < 0.05). The same trend was seen for calcium (not significant). The overall conclusion is that the model is a useful tool for mimicking the gastrointestinal tract of dogs. Parameters such as pH, transit time and enzyme activity can be mimicked and can be kept within a physiological range.[/fusion_toggle] [/fusion_builder_column][fusion_builder_column row_column_index="1_2" type="1_1" background_position="left top" background_color="" border_size="" border_color="" border_style="solid" spacing="yes" background_image="" background_repeat="no-repeat" padding="" margin_top="0px" margin_bottom="0px" class="" id="" animation_type="" animation_speed="0.3" animation_direction="left" hide_on_mobile="no" center_content="no" min_height="none"][s2If current_user_cannot(access_s2member_level0)] You need to register (for free) to download this article. Please log in/register here.[/s2If]

An Analysis of the Use of Dogs in Predicting Human Toxicology and Drug Safety

Jarrod Bailey, Michelle Thew and Michael Balls

Dogs remain the main non-rodent species in preclinical drug development. Despite the current dearth of new drug approvals and meagre pipelines, this continues, with little supportive evidence of its value or necessity. To estimate the evidential weight provided by canine data to the probability that a new drug may be toxic to humans, we have calculated Likelihood Ratios (LRs) for an extensive dataset of 2,366 drugs with both animal and human data, including tissue-level effects and Medical Dictionary for Regulatory Activities (MedDRA) Level 1–4 biomedical observations. The resulting LRs show that the absence of toxicity in dogs provides virtually no evidence that adverse drug reactions (ADRs) will also be absent in humans. While the LRs suggest that the presence of toxic effects in dogs can provide considerable evidential weight for a risk of potential ADRs in humans, this is highly inconsistent, varying by over two orders of magnitude for different classes of compounds and their effects. Our results therefore have important implications for the value of the dog in predicting human toxicity, and suggest that alternative methods are urgently required.

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