Physiologically Based Pharmacokinetic Modeling of Nanoparticles

Abstract

Nanoparticles are frequently designed to improve the pharmacokinetics profiles and tissue distribution of small molecules in order to prolong their systemic circulation, target specific tissue, or widen the therapeutic window. The multi-functionality of nanoparticles is frequently presented as an advantage but also results in distinct and complicated in vivo disposition properties compared to 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/toxicity of various types of drugs when coupled with pharmacodynamics (PD) 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.

Size‐Optimized Ultrasmall Porous Silica Nanoparticles Depict Vasculature‐Based Differential Targeting in Triple Negative Breast Cancer

“…Unlike our previous modeling approaches to study tissue disposition kinetics and tumor delivery efficacy of NPs, here we developed a multicompartment, semimechanistic model, which is a reduced physiologically based PK (PBPK) model, comprising a systemic blood pool, RES (i.e., liver and spleen), muscle, and a facultative tumor compartment (applicable for tumor‐bearing groups only), which represent the dominant distribution sites of the UPSNs in vivo, connected in an anatomical fashion via plasma (red arrows) and lymph (blue arrows) flow (Figure C and Figure S7, Supporting Information). In traditional PK modeling, organs are modeled as well‐stirred, black‐box like compartments with homogenous, time‐dependent exposure to administered drugs .…”

“…Semimechanistic Mathematical Modeling : This mathematical model, based on simplification of currently available PBPK, was formulated as a system of ordinary differential equations (ODEs) accounting for the transport and cellular interactions of NPs, to describe NP radioactivity kinetics (surrogate for NP mass kinetics) in the various compartments and sub‐compartments. A representative system of ODEs for a general compartment i containing all the three sub‐compartments (e.g., spleen and liver) is (see Figure S7, Supporting Information)…”

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles

“…Different pharmacokinetic models such as compartmental and especially physiologically based pharmacokinetic (PBPK) models have been developed to characterize the disposition of drugs in different organs and tissues, and especially in the liver, when they are administered in different types of nanoparticles (98,(106)(107)(108)(109)(110)(111)(112).…”

“…The mass balance of the drug throughout the body is defined through first-order differential equations. The distribution of the drug in each of the tissues can be perfusion-limited or diffusion-limited (112)(113)(114). Perfusion rate-limited kinetics occurs when blood flow limits tissue distribution.…”

<p>Silver Nanoparticles for the Therapy of Tuberculosis</p>

“…A clinical limitation of the usage of AgNP in TB therapy is based on the low tissue penetrability of large molecules following a non-intravenous route of administration. 246 Also in a lack of proper functionalization following an intravenous route of administration, a low intra-lesional accumulation is predictable considering the poorly vascularization of tuberculose-lung cavities present in chronic cases of tuberculosis. 247 Additionally, the persistence of mycobacteria in the nonvascularized necrotic material within the granuloma center can assure the persistence of a reservoir of viable mycobacteria in a biological environment largely inaccessible for large molecules and immune cells.…”