The primary objective of selecting appropriate nonclinical species for toxicology studies is to ensure the relevance and reliability of findings for human safety. Metabolism, which encompasses the chemical transformations occurring within living organisms, plays a critical role in this selection process.
Image Credit: BioIVT
This article looks at key considerations, regulatory guidance, and a real-world example that highlights and confirms the importance of metabolism when selecting species for toxicology studies of new chemical entities (NCEs).
The core goal of nonclinical toxicology studies
The principal goal of any nonclinical toxicology study is to assess the safety of an NCE prior to this progressing to human clinical trials. Investigating the NCE’s metabolic pathways in animals and humans in vitro typically ensures that the findings of a metabolism-related nonclinical study will be applicable to humans.
Regulatory guidance and considerations for species selection
Regulatory guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) outlines key principles for conducting nonclinical safety studies.
ICH M3 (R2) emphasizes the importance of using at least two mammalian species, including one non-rodent species, to improve the predictability of potential human toxicity.
The US Food and Drug Administration’s (FDA) Safety Testing of Drug Metabolites Guidance for Industry further underscores the need to consider metabolic profiles across species. Both quantitative and qualitative variations can occur, and the testing approach should align as closely as possible with the metabolic profile observed in humans.
Cross-species comparison of NCEs’ metabolism
Different species exhibit different metabolisms, which can substantially affect toxicology study outcomes. The table below compares metabolism between commonly used species, including humans, mice, rats, dogs, non-human primates (NHP), and miniature pigs. Each species presented has distinct metabolic characteristics.
Source: BioIVT
| Species |
Prominent Metabolic Traits |
| Human |
Single functional aldehyde oxidase (AO), no carboxylesterase in blood, dopamine oxidized by monoamine oxidase (MAO)-B, flavin monooxygenase (FMO)3 is the dominant hepatic FMO, quaternary N-glucuronide formation |
| Mouse |
Four functional AO genes, carboxylesterase activity in blood, dopamine oxidized by MAO-A, FMO1 is the dominant hepatic FMO, no quaternary N-glucuronide formation |
| Rat |
Four functional AO genes, carboxylesterase activity in blood, dopamine oxidized by MAO-A, FMO1 is the dominant hepatic FMO, no quaternary N-glucuronide formation |
| Dog |
No AO, no carboxylesterase in blood and intestine, quaternary N-glucuronide formation, FMO1 and FMO3 are the dominant hepatic FMOs |
| Miniature Pig |
One functional AO, no carboxylesterase in blood, FMO1 is the dominant hepatic FMO |
| NHP |
Two functional AOs, no carboxylesterase in blood, FMO3 is the dominant hepatic FMO, quaternary N-glucuronide formation |
Methodically determining the most appropriate species
It is important to employ a systematic approach when selecting the most appropriate species for a study. This includes a number of key factors.
- Test article structure analysis: Start by assessing the test article’s structure to understand its potential metabolism.
- Choose appropriate test systems: Employ appropriate test systems to determine metabolic clearance and metabolite profiles across species, for example, hepatocytes or subcellular fractions.
- Metabolite profile comparison: Metabolite profiles should be compared using in vitro and in vivo matrices across various species.
- Explore other aspects: Evaluate other aspects of optimal absorption, distribution, metabolism, excretion, and pharmacokinetics (ADME/PK) alongside pharmacology.
Adopting a methodical approach like the one outlined here will improve the chances of selecting species that accurately represent the metabolism of relevant human metabolites. This is key to enhancing nonclinical toxicology studies’ predictive value.
Clinical failure example: AO substrate
Real-world examples highlight the consequences of overlooking species-specific metabolic pathways.
In the clinical trial of BIBX1382, an aldehyde oxidase (AO) substrate, the drug failed to reach target plasma levels due to the emergence of a previously unrecognized metabolite in humans, along with a dose-limiting increase in liver enzymes.
Further investigation revealed that this unexpected metabolite was produced only in humans and rhesus monkeys, underscoring the critical importance of selecting species whose metabolism closely aligns with that of humans.
Conclusion: A holistic approach to species selection
In conclusion, metabolism plays a crucial role in species selection for nonclinical toxicology studies.
Understanding the complexities of metabolic pathways across species, adhering to regulatory guidance, and learning from past challenges are essential for ensuring the translatability of study outcomes to human safety.
A systematic, informed approach to species selection, grounded in metabolic knowledge, enhances the reliability and relevance of toxicology studies in the development of NCEs.
Acknowledgments
Produced from materials originally authored by BioIVT.
About BioIVT
BioIVT, formerly BioreclamationIVT, is a leading global provider of high-quality biological specimens and value-added services. We specialize in control and disease state samples including human and animal tissues, cell products, blood and other biofluids. Our unmatched portfolio of clinical specimens directly supports precision medicine research and the effort to improve patient outcomes by coupling comprehensive clinical data with donor samples.
Our Research Services team works collaboratively with clients to provide in vitro hepatic modeling solutions. And as the world’s premier supplier of ADME-Tox model systems, including hepatocytes and subcellular fractions, BioIVT enables scientists to better understand the pharmacokinetics and drug metabolism of newly discovered compounds and the effects on disease processes. By combining our technical expertise, exceptional customer service, and unparalleled access to biological specimens, BioIVT serves the research community as a trusted partner in ELEVATING SCIENCE®.
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