Physiologically Based

Pharmacokinetic (PBPK)

modeling of Nanoparticles

Ankit Dhaundiyal

M.S. (Pharm.), 2nd Year

13PIM1833

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Physiologically Based Pharmacokinetic (PBPK) Models

• Physiologically based pharmacokinetic (PBPK) modeling is amathematical modeling technique for predicting the absorption,distribution, metabolism and excretion(ADME) of synthetic ornatural chemical substances humans and other animal species.

• used in pharmaceutical research and drug development

• PBPK models strive to be mechanistic by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes.

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Physiologically Based Pharmacokinetic (PBPK) Models

• usually multicompartment models, with compartmentscorresponding to predefined organs or tissues, withinterconnections corresponding to blood or lymph flows (morerarely to diffusions).

• system of differential equations for concentration or quantity ofsubstance on each compartment can be written, and itsparameters represent blood flows, pulmonary ventilation rate,organ volumes etc.

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Characteristics of PBPK Models• Compartments are to represent the amount or concentration of the

chemical in a particular tissue.

• Model incorporates known tissue volumes and blood flow rates; thisallows us to use the same model across multiple species.

• Similar tissues are grouped together.

• Compartments are assumed to be well-mixed.

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Example of Compartment in PBPK Model

• QK is the blood flow into the kidney.

• CVK is the concentration of drug in the venous blood leaving the kidney.

QK CVKKidney

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Example of Compartment in PBPK Model

• CK is the concentration of drug in the kidney at time t.

• CVK is the concentration of drug in the venous blood leaving the kidney at time t.

• QK is the blood flow into the kidney.• VK is the volume of the kidney.

K

KKKK

V

CVCQ

dt

dC

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PBPK Model of Nanoparticles

• Need to understand their fate within human body

• Nanoparticles entrance into body classified in two ways :

a) Unintentional

b) Intentional

• For both, Toxicity needs to evaluated carefully

• An exponential growth has been seen in the field ofnanoaprticles

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PBPK Model of Nanoparticles• PBPK models have been listed as one of the current quantitative

support tools for investigation of nanoparticle hazards assessment asspecified in the Organization for Economic Cooperation andDevelopment (OECD) guideline and the new European Unionregulatory framework, Registration, Evaluation, and Authorization ofChemicals (REACH)

• Physiological processes of nanoparticles could be much morecomplex, involving opsonization in the blood, cellular recognitionand internalization, enzymatic degradation, physical propertychanges

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ADME of Nanoparticles• Absorption

• Distribution:• 1) Blood : Protein binding to nanoparticles surfaces (Opsonization)

Physicochemical properties of “NP-Protein complex” are different from nanoparticles itself

Phagocytosis of NP by macrophages

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ADME of Nanoparticles• Blood vessel fenestration : 1) Continous

2) Fenestrated

3) Discontinous

• Blood Vessel supply : 1) Quickly perfused

1) Slowly perfused

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ADME of Nanoparticles• 2) Reticuloendothelial System:

o Monocytes circulating in the blood

o Kupffer cells in the tumor

o Reticular cells in lymph nodes, bone marrow

o Fixed macrophages of various connective tissues

o Surface modification using hydrophilic molecules . Eg. PEG

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ADME of Nanoparticles• 3) Tumors :

• Leaky, tortuos and dilated blood vessels

• High vascular density, vascular leakiness

• Leads to enhanced permeability and retention (EPR) effect for NP.

• By avoiding RES , prolong blood circulation, leading to EPR

• Use of Active targeting . i.e. antibody or peptide.

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ADME of Nanoparticles• Metabolism :

• NP broken down in the lysosomes of the macrophages cells of the RESafter being internalized or the hydrolytic degradation of NPs in the invivo aqueous environment

• Also, upon internalization, biological molecules attached to NP surfacesare degraded within the endosomal compartment through peptidecleavage by the protease Cathepsin L.

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ADME of Nanoparticles• Excretion : Liver & Kidney

Lungs, Breast Milk, Sweat

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Transportation Kinetics• Very complicated and still poorly understood.

• NPS experience processes in body like cell interaction (adhesion,endocytosis, exocytosis, and diffusion).

• Eg: Magnetic NPs and macrophages

Two way : binding of NP onto cell surface , then cell internalization

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Software for PBPK Modeling

• GastroPlusTM (Simulations Plus Pvt. Ltd.)

• SimCYP (CERTARA)

• BioDMET (General Electric Global Research Center)

• acslX (acslX Pharmaceuticals)

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REFERENCES• Mingguang li, Khuloud T. Al-Jamal, Kostas Kosterelos and Jodhua Relneke.

Physiologically Based Pharmacokinetic Modeling of Nanoparticles, ACS Nano. Vol4 pp 6303-6317 (2010).

• Krishnan K and Andersen ME (2001) Physiologically Based PharmacokineticModeling in Toxicology. In Principles and Methods in Toxicology, 4th Edition, A.Wallace Hayes (Ed), Taylor & Francis, Philadelphia. pp 193-241.

• Himmelstein KJ and Lutz RJ (1979) A Review of the Applications of Physiologically Based Pharmacokinetic Modeling. J Pharmacokinet Biopharm 7(2):127-145.

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4/10/2015 36Thanks a lot……….