The Important Role That In-Vivo Toxicology Studies Play in Drug Discovery & Development

Toxicology Studies

Escalating drug development costs and a downward trend in drug approvals has been a fundamental concern for drug discovery and development initiatives. This challenge is primarily credited to attrition at later stages of drug development. Hence, most of the focus is on  developing  and applying novel technologies in the development phases. However, emphasizing  current applications such as in vivo approaches can help drug developers and toxicology services overcome many of these developmental barriers.

The primary goal of in vivo toxicology studies is to determine potential adverse effects in study animals for extrapolating safety and efficacy concerns for human studies or the feasibility of the drug compound for further development. Besides, in vivo toxicology studies can be performed parallelly to evaluate toxic effects and correlate them to preclinical findings. Hence, let us dive deep and understand why in vivo toxicology studies are vital for drug discovery and development projects.

The importance of in vivo toxicology studies

While interpreting toxicity endpoints is straightforward in nonclinical studies, the extrapolation of animal findings to human models is more complex. This difference is not only because of discrepancies in pathophysiology and biology but also due to intrinsic differences in ADME properties. Several studies have demonstrated rodent-specific toxicities such as bladder tumor formation and thyroid hormone regulation, occurring due to disparities in drug metabolism. However, understanding drug mechanisms in animal models produces vital risk assessment profiles necessary for determining early doses in human trials.

Moreover, the risk assessment profiles can further help decode any lack of relevance found in human studies. Improving risk profiles and selecting the right candidate drug cannot be achieved solely through regulatory toxicity studies or increasing the number of test animals. It needs a thorough understanding of the underlying mechanism of drug toxicity. Hence, adequate early in vivo toxicology studies can help reap maximum benefits and identify potential drug compounds.

Traditionally, in vivo toxicology studies are preceded by several ancillary analyses. These primary studies provide key information about drug efficacy through in vivo and in vitro approaches and PK properties based on single-dose toxicity study and in vitro evaluations. However, these initial acute toxicity study approaches that typically evaluate pharmacokinetics and efficacy features lack in revealing dose-limiting toxicity data. Hence,  repeated dose toxicity studies are often conducted to assess toxicity under repeat-dose conditions. These studies are multiple ascending dose (MAD) studies where sponsors increase the drug levels ascendingly and evaluate toxicity. Such dose range-finding studies help determine the maximum tolerated dose levels in animal models.

Furthermore, well-tolerated doses from dose-ranging studies are parallelly evaluated in repeated dose toxicity studies to accumulate more extensive data for regulatory submissions. These additional data include physiological measures such as clinical observations and weight, microscopic histological findings, and clinical and hematology evaluations.

The road ahead for in vivo toxicology studies in drug discovery and development

Proving toxicity in animals is necessary before moving forward to human clinical trials. Hence, in vivo clinical toxicological analysis in animals forms the basis for assessing risk and safety profiles early in drug development endeavors.

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By Michael Caine

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