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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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生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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/
生物制药工程 夏玉琼 西安电子科技大学
Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
10http://immunopaedia.org.za/index.php?id=77
生物制药工程 夏玉琼 西安电子科技大学
IV administration
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No presystematic degradation Achieve the highest concentration in the biological
system A bolus dose Short half-life
生物制药工程 夏玉琼 西安电子科技大学
IM and SC administration
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Pre-systematic degradation
Lower bioavailability Longer half-life
生物制药工程 夏玉琼 西安电子科技大学
SC administration
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Blood capillaries or lymphatic vessels
Macromolecules(>16 kDa) are predominantly absorbed into lymphatics
Efficient in targeting lymphoid cells
生物制药工程 夏玉琼 西安电子科技大学
Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
From vascular space to interstitial space
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Endocytosis
http://en.wikipedia.org/wiki/File:Endocytosis_types.svg
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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PK/PD modeling
Simulate time course of effect of a drug
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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Indirect response PK/PD modelsA time-consuming indirect response
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
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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
生物制药工程 夏玉琼 西安电子科技大学
40 Con
cent
ratio
n�in
�pla
smaC
ount
s�of
�RBC
Retic
uloc
ytes
�(网
状细
胞)
生物制药工程 夏玉琼 西安电子科技大学
Outline
41
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
生物制药工程 夏玉琼 西安电子科技大学
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Complex response modelsIndirect response model
Indirect link model
生物制药工程 夏玉琼 西安电子科技大学
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
生物制药工程 夏玉琼 西安电子科技大学
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.
生物制药工程 夏玉琼 西安电子科技大学
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