Do pharmacodynamics and pharmacokinetics of the drug in animals are the same as in human?

Question

I'm trying to understand the purpose of different clinical trial phases, and the following question comes into my mind :

Do pharmacodynamics and pharmacokinetics of the drug in animals are the same as in human?

The reason I asked this question is that our professor said that pharmacodynamic and pharmacokinetic studies are performed during pre-clinical studies (in animals), as well as during clinical trial's phase 1. The answer I was thinking about is that animal's physiology cannot be the same as human's physiology, thus, pharmacological profils should be different.

I just want to know more about this and feed my curiosity.

Answer 1

Drug metabolism in humans is different than animal models.

Here is one example: http://www.ncbi.nlm.nih.gov/pubmed/17125407

The link is a review where they compare different animal models to humans with a focus on CYP enzymes commonly involved in drug metabolism. While they describe similarities, they note:

CYP2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans

Essentially your instincts that different species have different pharmacology is accurate and based on the many genetically-based differences in the drug processing machinery.

Similarly, there are differences in drug metabolism between humans with different genetic backgrounds, which is the basis for pharmacogenetics (https://en.wikipedia.org/wiki/Pharmacogenetics).

More recently, differences in gut microbes have also been raised as contributory factors (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3529681/). In this case, identical twins with different diets could conceivably have different pharmacokinetics.

Tying this all back, the reason human drug trials are needed is because animal and tissue culture models are necessary, but insufficient to predict drug efficacy or safety.

Answer 2

You are correct. The pharmacokinetics are different, but also quite similar. The good thing is that we know what most of those differences are and can account for them when we scale models from animal species to humans.

Conducting pharmacokinetic studies in animals before conducting studies in humans is necessary and useful for a few reasons.

1. The Dose-Toxicity relationship can be assessed. We will also get a better idea of what specific toxic effects to look for.
2. Scaled physiologically-based pharmacokinetic models appropriately predict pharmacokinetics in humans from animal data.
3. Variability can be assessed (i.e. if I administer a certain dose, how much variation can I expect in concentration profiles for a group of individuals?)

Physiologically-based pharmacokinetic models use a bottom-up rather than a top-down approach to modelling. This approach allows accurate interspecies scaling simply by changing the system parameters according to the species of interest. To begin, a virtual animal or person is created with organ volumes, blood flow rates, enzyme activities, etc. as defined in literature. These are the system parameters. Next, drug-specific parameters (solubility, charge, partition coefficients) are determined from literature or experimentally where possible. Finally, all processes which are theorized to affect the drug's absorption, distribution, metabolism and excretion are described with a system of ordinary differential equations, using the system and drug-specific parameters. Any unknown drug-specific parameters can be fitted to animal data at this time. It is useful to be able to determine estimates for drug-specific parameters with animal models that can be later applied to human models.

The model is validated by comparing the model simulations with actual experimental data from animals (Animal PK Trials!). If the model makes accurate predictions, all we have to do is change the system parameters (organ volumes, blood flow rates, enzyme activites, etc.) from animal values to human values, while keeping the drug-specific parameters constant, and the system of ODEs will make a good prediction of the pharmacokinetics in humans. Of course, this is a simplified methodology. Occasionally the model equations or drug-specific parameters must be changed between species to account for some physiologic differences. This process is called interspecies scaling and considerable research efforts have been put forward to standardize it.

These conclusions can be used to find an ideal First-in-Human dose. PBPK modelling gives great insights into more than just First-in-Human trials. Pediatric and Geriatric simulations are also very useful. By changing the system parameters from adult to pediatric or geriatric (recognizing that humans change a lot with age), we can make guesses about the doses that are safe for children or the elderly. The FDA now requires PBPK modelling to be done for its submissions. All of this starts with animal PK trials.