5 Pharmacokinetics and pharmacodynamics of …web.xidian.edu.cn/yqxia/files/20140222_213352.pdfPharmacokinetics 5 Change in the concentration of a drug in plasma or blood) Include

By Yuqiong Xia2014

Pharmacokinetics and pharmacodynamics

Pharmaceutical Biotechnology

Keywords

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Pharmacokinetics, pharmacodynamics, dose Metabolism, excretion Lymphatic, vascular, renal, hepatic, bile, lysosome

生物制药工程夏玉琼西安电子科技大学

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The dose-concentration-effect relationship生物制药工程夏玉琼西安电子科技大学

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Pharmacokinetics

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Change in the concentration of a drug in plasma or blood)

Include drug absorption, distribution, metabolism and excretion

“what the body does to the drug”

http://www.animalhealth.bayer.com/fileadmin/images/baytril/food_animals/NT_3_2_1.gif

timeSeru

m c

once

ntra

tion


Pharmacodynamics

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Drug effect or toxicity, usually at the assumed site of drug action

“what the drug does to the body”

http://blog.palmpartners.com/pharmacodynamics/


Outline

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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization

Pharmacodynamics of protein therapeutics


Half-life

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The half-life of peptide and protein drugs may often be predicted from their physiological function

Peptides or proteins Elimination half-life

Peptides having hormone activity Very shortinsulin 26 min at 1 U/kgAlbumin having transport task Several daysImmunoglobulin Several days


Oral administration

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To overcome the low bioavailability of oral route Encapsulating drugs in micro- or nanoparticles Chemical modifications and conjugations Coadministration of protease inhibitors

http://www.microparticles.de/metal_coated_particles.htmlhttp://en.wikipedia.org/wiki/Beta-peptide


10http://immunopaedia.org.za/index.php?id=77


IV administration

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No presystematic degradation Achieve the highest concentration in the biological

system A bolus dose Short half-life


IM and SC administration

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Pre-systematic degradation

Lower bioavailability Longer half-life


SC administration

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Blood capillaries or lymphatic vessels

Macromolecules(>16 kDa) are predominantly absorbed into lymphatics

Efficient in targeting lymphoid cells


Outline

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Distribution volume

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Generally, limited to extracellular space Sometimes larger Active tissue uptake Bind to intra- or extravascular proteins Positive proteins bind to negative membrane stronger


From vascular space to interstitial space

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Convection: due to the hydrostatic pressure gradient

Convection brings drug from vessel to tissue

Lymph drainage remove drug from tissue

http://o.quizlet.com/10xzJX6NDmTljlJmL7u0yg.jpg


From vascular space to interstitial space

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Endocytosis

http://en.wikipedia.org/wiki/File:Endocytosis_types.svg


Effect of Protein binding on distribution

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Affects the fraction of a drug available to exert pharmacological activity

Prolongs protein circulation time Enhances protein clearance


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Effect of protein (Ab) binding on distribution生物制药工程夏玉琼西安电子科技大学

Effect of receptor-mediated uptake on distribution

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Result in therapeutically effective tissue concentrations, but a relatively small volume of distribution

Vessel

Drug

Tissue Receptor


Outline

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Proteolysis

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Degradation from proteins to peptides, from peptides to amino acids

http://pubs.niaaa.nih.gov/publications/arh27-4/317-324.htm


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Proteolysis depends on MW生物制药工程夏玉琼西安电子科技大学

Gastrointestinal protein metabolism

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Major site, due to high proteolytic enzyme activity Mostly for orally administrated drugs Parental drugs may also be metabolized in the

intestinal mucosa following intestinal excretion

http://www.uofmmedicalcenter.org/healthlibrary/Article/40233


Renal protein metabolism and excretion

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Major route for small proteins (<=60 kD) Undergo glomerular filtration, most efficient for

proteins <= 30 kD

http://zlgc.xxmu.edu.cn/eol/homepage/course/course_onlinepreview.jsp?_style=page6&countadd=1&menuId=62326&resid=121571


Hepatic protein metabolism

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Major route Protein enter cytosol by diffusion, metabolized by

microsomal enzymes（微粒体酶） Protein enter by carrier system, metabolized in bile Protein enter through receptor-mediated uptake,

metabolized by lysomehttp://www.webmd.com/digestive-disorders/picture-of-the-liver


Outline

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Chemical modifications

Delete, add or replace amino acids

http://upload.wikimedia.org/wikipedia/commons/thumb/c/c9/Peptide-Figure-Revised.png/780px-Peptide-Figure-Revised.pnghttp://www.piercenet.com/media/Glycosylation-types-530px1.jpg

Glycosylation

Conjugate to polymer


Outline

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Pharmacokinetics of protein therapeutics Pharmacodynamics of protein therapeutics Direct link PK/PD models Indirect link PK/PD models Indirect response PK/PD models Cell lifespan models Complex response models


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PK/PD modeling

Simulate time course of effect of a drug


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Direct link PK/PD models

Clearance

Peripheral compartment

Central compartment

Emax: maximum achievable effectEC50: concentration of the drug that produced half of the maximum effectn: Hill coefficient

The relationship between concentration in plasma and in effect site is constant


Outline

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Indirect link PK/PD models

CL1e equibrium clearanceCLe0 transfer clearance

There is a delay between concentrations in plasma and the effect site

Peripheral compartment

Central compartment


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Indirect link PK/PD modelsThere is a delay between concentrations in plasma and the effect site

Concentration in plasma Concentration in effect site


Outline

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Indirect response PK/PD modelsA time-consuming indirect response


Outline

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Process of erythropoiesis（红细胞生成）

多能干细胞

红细胞祖细胞

红细胞前体

白细胞血小板

爆炸红系集落形成单位

红系集落形成单位

红细胞

网状红细胞

红细胞

祖细胞1

祖细胞2


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Cell lifespan models of rhEPO（重组促红细胞生成素）

祖细胞1

祖细胞2

网状红细胞

红细胞Stimulation

Inhibition


40 Con

cent

ratio

n�in

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ount

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Retic

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�（网

状细

胞）


Outline

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Complex response modelsIndirect response model

Indirect link model


Summary

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Pharmacokinetics Absorption by oral/IV/SC/IM route Distribution Elimination by GI, liver, kidney Chemical modification

PK/PD model Direct link PK/PD model Indirect link PK/PD model Indirect response PK/PD model


Homework 4

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Fill in the blanks Now a patient is being treated with protein drug A using

IV injection. Protein drug A will first enter ( ), and then enter interstitial space by ( ). Some of the drug will reach ( ) to make effect. The distribution volume should be ( ) (larger than, smaller than or equal to)that of extracellular space.

Suppose there is a constant relationship between the drug concentration in plasma and in effect site, the PK/PD process can be analyzed using ( ) PK/PD model.


Documents

5 Pharmacokinetics and pharmacodynamics of …web.xidian.edu.cn/yqxia/files/20140222_213352.pdfPharmacokinetics 5 Change in the concentration of a drug in plasma or blood) Include