Graphic representation of a physiologically based whole body model. Blood flows, Q, and concentration, , of a substance of interest are depicted. PBPK models strive applied biopharmaceutics and pharmacokinetics 6ed pdf be mechanistic by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes.
That is true for both toxicity risk assessment and therapeutic drug development. Indeed, the description they make of the body is simplified and a balance needs to be struck between complexity and simplicity. An example of a 7-compartment PBPK model, suitable to describe the fate of many solvents in the mammalian body, is given in the Figure on the right. It led, however, to computations intractable at that time.
By 2010, hundreds of scientific publications have described and used PBPK models, and at least two private companies are basing their business on their expertise in this area. The model equations follow the principles of mass transport, fluid dynamics, and biochemistry in order to simulate the fate of a substance in the body . Bone can be excluded from the model if the substance of interest does not distribute to it. Drug distribution into a tissue can be rate-limited by either perfusion or permeability. Perfusion-rate-limited kinetics apply when the tissue membranes present no barrier to diffusion. Blood flow, assuming that the drug is transported mainly by blood, as is often the case, is then the limiting factor to distribution in the various cells of the body. That is usually true for small lipophilic drugs.
The above equations include only transport terms and do not account for inputs or outputs. Those can be modeled with specific terms, as in the following. Modeling inputs is necessary to come up with a meaningful description of a chemical’s pharmacokinetics. The following examples show how to write the corresponding equations. In the absence of a gut compartment, input can be made directly in the liver. However, in that case local metabolism in the gut may not be correctly described.
More sophisticated gut absorption model can be used. In those models, additional compartments describe the various sections of the gut lumen and tissue. Intestinal pH, transit times and presence of active transporters can be taken into account . The absorption of a chemical deposited on skin can also be modeled using first order terms. More complex diffusion models have been published .