The subject of animal testing by the pharmaceutical industry is a contentious one. While no one could reasonably dispute the countless advances that in vivo testing has made possible, the potential ethical ramifications are still hotly debated. Nevertheless, Pharmacokinetic (PK) and Toxicokinetic (TK) studies rely heavily on animal models.
Yet despite their ubiquity in drug development, animal models are not always reliable predictors of either a new product’s efficacy or any potential health risks it may present. Countless drugs that seemed effective during preclinical trials and did not cause adverse side effects in animal cohorts later proved to be ineffective or even dangerous to human subjects.
Anatomical, physiological, and metabolic differences between species accounts for this. Furthermore, certain disorders which affect both non-human and human animals can manifest different symptoms and follow different pathways, depending on the species.
Even when differences in biomarkers are taken into account, it can be hard to predict how closely human reactions to a drug will mirror the animal model’s, if at all. When PK and TK studies fail to identify potential toxicity, the results can be disastrous. Human subjects are put at risk, and the drug may need to be reformulated from scratch.
Given the potential costs of such a setback, the suboptimal role animal models play in accurately predicting human toxicity, and increasing regulations regarding the welfare of lab animals, it is small wonder all eyes are on emerging alternatives to in vivo testing.
Chemosynthetic liver technology remains in development, but has the potential to transform how we study toxicology.
In 2014, Dr. Mukund Chorghade impressed the 247th National Meeting & Exposition of the American Chemical Society (ACS) by presenting on the so-called “chemosynthetic liver” he has developed for metabolic profiling. Instead of using animal subjects to test the breakdown of drugs, his in vitro technology utilizes catalysts that mimic enzymes found in the human body.
By delivering comparable metabolites as animal models but on a quicker timeline and with a more comprehensive metabolic profile, this technology has the potential to improve the safety of clinical trials while simultaneously reducing the time and financial investment of drug development.
While this “chemosynthetic” technology remains proprietary at present, its development signals a possible sea change in the way the pharmaceutical industry approaches toxicology. If there are safer, more affordable, and more accurate testing methods, why not develop them?
Another recent in vitro advance challenges toxicological assumptions.
Preliminary toxicity testing has long been conducted in vitro, but invariably as an initial phase before stepping up to animal models. Several recent studies point to the possibility of dispensing with in vivo preclinical trials altogether, instead relying on dependable and repeatable in vitro solutions.
While in vitro studies once employed simple mammalian cells or cultured bacteria, dedicated scientists are now creating far more complex research models. One international research team recently developed a co-culture model that successfully mimicked the human intestine in both healthy and diseased states.
In vitro intestine models are nothing new, but rarely with such complexity of cell models. The depth and breadth of data yielded by the study begs the question if developing more complex in vitro models might one day replace animal studies altogether.
“In Silico” modeling provides another window into toxicology research.
Computational modeling has been used in drug discovery and development since the inception of the technology, but generally as a compliment to in vivo testing and not as a replacement. “Pathway-based predictive approaches for non-animal assessment of acute inhalation toxicity,” a paper published Volume 52 of Toxicology in Vitro, did just that, relying solely on in silico and in vitro trials.
The authors of the study overtly state that their reason for using computational modeling instead of animal models stemmed from the fact that the results of animal testing can not always be accurately or consistently extrapolated to human subjects. For this particular trial, advances in technology and computational biology provided far more reliable data that traditional in vivo testing could have.
This study is a harbinger of where the industry is directed. The global toxicology testing services market was recently valued at over six billion dollars, and the ongoing development of predictive toxicological testing technologies plays a substantial role in that evaluation. If a drug could be safely brought to market without animal testing the financial savings would be incalculable.
For the time being, animal models will continue to play an essential role in the pharmaceutical industry. As new technologies emerge and old in vitro methods are updated and refined, however, that time may grow short.