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. 225
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. 432