PBPK Modelling of Intracellular Drug Delivery Through Active and Passive Transport Processes

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Physiologically based pharmacokinetic (PBPK) models describe adsorption, distribution, metabolisation and excretion (ADME) of drugs in the body of an organism based on a large amount of prior anatomical and physiological knowledge. In contrast to compartmental pharmacokinetic modeling which uses rather empirical model structures, PBPK models aim for a detailed mechanistic representation of physiological processes underlying drug pharmacokinetics within the body. That means that the relevant organs or tissues of an organism are explicitly represented in a PBPK model. Organs in PBPK models are usually divided in subcompartments such as plasma, interstitial space, intracellular space and red blood cells. Mass transfer between the different compartments which ultimately governs intracellular drug delivery is quantified either by so-called distribution models for the calculation of organ-plasma partition coefficients or by permeability-surface area products quantifying passive diffusion, respectively. Notably, both types of calculation methods are parameterized based upon the physicochemical properties of the investigated drug, respectively. These properties include amongst others lipophilicity and the molecular weight of the compound. Additional physiological information ranging from the whole body level (e.g. organ volumes, blood flow rates, tissue composition) to relative tissue-specific protein abundance is explicitly provided in the model. PBPK models are nowadays routinely used to analyze pharmacokinetics in drug development Due to the large amount of mechanistic information which is implicitly provided in the structural equations, PBPK models are in particular well-suited for both in-depth analyses of ADME processes underlying drug pharmacokinetics as well as for extrapolation to novel indications, patient populations or treatment designs. In this review we will present and discuss calculation methods used in PBPK model to describe and to quantify intracellular drug delivery.