Animals do not excrete drugs like humans – yet we assume they do

Before the safety of a new drug is tested in human volunteers, animal models are used to determine an appropriate first-in-human dose. A standard test parameter is renal clearance, a measure of how fast a substance is excreted via the kidneys. This is a key determinant of drug doses: the lower the clearance, the lower the drug dose should be in order to avoid intoxication. First-in-human doses are estimated based on animal clearance and body weight. However, this approach proceeds on the assumption that humans and animals excrete drugs in the same way. Humans might be animals, but are animals human enough?

The power of ¾

Researchers from Utrecht University, the University Medical Center Utrecht and Radboud University Medical Center in Nijmegen set out to find an answer to this question – without the use of a single animal. Instead, the team of Professor Roos Masereeuw applied the principles of systematic reviewing to extract renal clearance data of 20 drugs with diverse properties for humans and several animal species from existing literature.

Using this data, they built on one of the few biological laws that exist: an animal’s metabolic rate scales to the ¾ power of the animal’s mass. Their argument: the kidneys should adjust to metabolic rate for effective waste removal, which implies that renal clearance, too, scales to the ¾ power of the animal’s mass – unless there are differences between humans and animal models in the way that drugs are being excreted. While most studies report deviating exponents to best predict human clearance based on animal data, the researchers used the exponent of ¾ to identify interspecies differences in renal clearance. They publish their findings in Drug Discovery Today.

Surprisingly, rats turned out to be the least reliable. “This is worrisome because rats are the most commonly used animal models in drug testing.

Rats overestimate human drug clearance

“The drug clearance values of humans and five animal models aligned surprisingly well with the exponent of ¾, which confirmed our hypothesis”, says Katja Jansen from Utrecht University, first author of the publication in Drug Discovery Today. When looking closer at the prediction accuracies of different animal species, however, the researchers identified some prediction errors. Surprisingly, rats turned out to be the least reliable. “This is worrisome because rats are the most commonly used animal models in drug testing”, explains Carla Pou Casellas from UMC Utrecht, who is shared first author.

“The identified differences can arise from differences beyond renal clearance but that does not change the fact that rats are suboptimal models for human predictions.” Although the study results suggested general reliability for clearance values derived from mice, rabbits, dogs, and monkeys, the authors stressed that it is important to interpret the outcomes with caution since less data were available for these species.

This study design can help in the reduction of animal experiments in two ways

An innovative animal-free approach

The systematic use of existing data for a meta-analysis as performed by Professor Masereeuw’s research team is a novel approach to answer new research questions without the need to perform new experiments. This study design can help in the reduction of animal experiments in two ways: as animal-free research method itself, and as prospective aid for the selection of adequate animal models in drug testing.

The replacement of animal experiments is both a societal and political ambition, to which Utrecht University is contributing with U-AIM (Utrecht Advanced In Vitro Models Hub), a ‘one-stop shop’ where high potential in vitro models are being developed, validated and transitioned to stakeholders. However, until in vitro models can fully replace animals, researchers will rely on animal data. The meta-analysis in question shows that animals might not excrete drugs exactly like humans; yet this assumption is what enables researchers to derive at least an estimation of first-in-human doses in daily practice.

Publication

Humans are animals, but are animals human enough? A systematic review and meta-analysis on interspecies differences in renal drug clearance. Katja Jansen*, Carla Pou Casellas, Lucianne Groenink*, Kimberly Wever, Roos Masereeuw*. Drug Discovery Today (2020).

*Authors affiliated with Utrecht University