Physiologically Based Pharmacokinetic Modeling of Nanoparticles

Abstract

Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules to prolong their systemic circulation, target specific tissue, or widen the therapeutic window. The multifunctionality of nanoparticles is frequently presented as an advantage but also results in distinct and complicated in vivo disposition properties compared with a conventional formulation of the same molecules. Physiologically based pharmacokinetic (PBPK) modeling has been a useful tool in characterizing and predicting the systemic disposition, target exposure, and efficacy and toxicity of various types of drugs when coupled with pharmacodynamic modeling. Here we review the unique disposition characteristics of nanoparticles, assess how PBPK modeling takes into account the unique disposition properties of nanoparticles, and comment on the applications and challenges of PBPK modeling in characterizing and predicting the disposition and biological effects of nanoparticles.

Keywords: PBPK; efficacy; mononuclear phagocytic system; nanoparticle disposition; tissue distribution; toxicity.

Figure 1.

A generic PBPK model (A) and two types of tissue model structure (B). Qi: blood or plasma flow; k_p: tissue partitioning coefficient, namely concentration ratio between tissue and blood at steady-state; PS: membrane permeability coefficient; CL_hep: hepatic clearance; CL_renal: renal clearance.

Figure 2.

Implementation of PBPK models.

Figure 3.

A specialized PBPK model for drugs encapsulated in nanoparticles. Compared to the generic PBPK model for small molecules as shown in Figure 1, this specialized model for nanodrugs consists of two layers of PBPK models for each of nanoparticles and released small molecules. The two layers are connected by drug release (orange arrows). Drug release is tissue-specific; the presence of phagocytic cells and local stimuli (e.g. low pH in tumors) affect drug release (thicker orange arrows). For small molecules, the PBPK modeling layer is the same as the model in Figure 1. For nanoparticles, due to the large size, tissue distribution is convection-driven (unidirectional blue arrows) in most tissues. One exception is the tumor, where passive diffusion is the major distribution mechanism because the high interstitial pressure in solid tumors limits effective convection. The enhanced accumulation of nanoparticles in the lung, spleen, and liver is associated with the leaky vasculature structures and MPS sequestration, which is depicted by the thicker blue arrows. High tumor accumulation of nanoparticles is ascribed to the EPR effect. This specialized model also includes the lymphatic systems for recycling nanoparticles (blue dashed arrows) from the interstitial space.