By YuqiongXia 3/17/2016 -...
Transcript of By YuqiongXia 3/17/2016 -...
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By Yuqiong Xia3/17/2016
Pharmacokinetics and pharmacodynamics
Pharmaceutical Biotechnology 西安电子科技大学 夏玉琼
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Keywords
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Pharmacokinetics, pharmacodynamics, dose Metabolism, excretion, protease Lymphatic, vascular, renal, hepatic, bile, lysosome
西安电子科技大学 夏玉琼
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The dose-concentration-effect relationship西安电子科技大学 夏玉琼
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西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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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/
西安电子科技大学 夏玉琼
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Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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10http://immunopaedia.org.za/index.php?id=77
西安电子科技大学 夏玉琼
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IV administration
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No pre-systematic degradation Achieve the highest concentration in the biological
system A bolus dose Short half-life
西安电子科技大学 夏玉琼
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IM and SC administration
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Pre-systematic degradation
Lower bioavailability Longer half-life
西安电子科技大学 夏玉琼
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SC administration
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Blood capillaries or lymphatic vessels
Macromolecules(>16 kDa) are predominantly absorbed into lymphatics
Efficient in targeting cells
西安电子科技大学 夏玉琼
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Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
西安电子科技大学 夏玉琼
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Distribution volume of protein drugs
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Generally, limited to extracellular space Limited mobility of proteins Impaired passages through bio-membane
Sometimes different Bind to intra- or extravascular proteins, larger
distribution volume Active tissue uptake, smaller distribution volume
西安电子科技大学 夏玉琼
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From vascular space to interstitial space
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Convection due to the hydrostatic
pressure gradient brings drug from vessel to
tissue Lymph drainage remove
drug from tissue
http://o.quizlet.com/10xzJX6NDmTljlJmL7u0yg.jpg
西安电子科技大学 夏玉琼
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Less important way from vascular to interstitial
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transcellular migration via endocytosis
http://en.wikipedia.org/wiki/File:Endocytosis_types.svg
西安电子科技大学 夏玉琼
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intra- or extravascular protein binding on distribution
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Affects the fraction of efficient drug Generally, free drugs are efficient while protein
bound drugs are not
Prolongs protein circulation time Bind to proteins with long circulation time
Enhances protein clearance Being recognized by some immuno-proteins
西安电子科技大学 夏玉琼
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Effect of protein (Ab) binding on distribution西安电子科技大学 夏玉琼
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Active uptake (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
西安电子科技大学 夏玉琼
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Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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Proteolysis depends on MW 西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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Pathways of renal metabolism of peptides and proteins
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Either (a) intraluminal metabolism or (b) tubular reabsorption and (c) peritubular excretion
西安电子科技大学 夏玉琼
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Three mechanisms
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Intraluminal metabolism Glomerular filtration intraluminal metabolism, predominantly by exopeptidases in the luminal brush border
membrane of the proximal tubule The resulting peptide fragments and amino acids are reabsorbed into the systemic
circulation Apply to small linear peptides such as glucagon and LH-RH
Tubular reabsorption with intracellular lysosomal metabolism glomerular filtration of larger, complex peptides and proteins reabsorption into endocytic vesicles in the proximal tubule hydrolysis into small peptide fragments and amino acids E.g. IL-2, IL-11, growth hormone, and insulin
Peritubular extraction with intracellular lysosomal metabolism peritubular extraction of peptides and proteins from post-glomerular capillaries Intracellular metabolism
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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Outline
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Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization
Pharmacodynamics of protein therapeutics
西安电子科技大学 夏玉琼
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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
1. preventing the protein from being recognized by the immune system 2. reducing its elimination via glomerular filtration or proteolytic enzymes
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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PK/PD modeling
Simulate time course of effect of a drug
西安电子科技大学 夏玉琼
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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 C: drug concentration in plasma
The relationship between concentration in plasma and in effect site is constant
Q: distribution clearance
clearance
dose
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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Indirect link PK/PD models
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There is a delay between concentrations in plasma and the effect site Plasma concentration maxima occur before effect
maxima Effect intensity may increase despite decreasing
plasma concentrations Effect may persist beyond the time drug
concentrations in plasma are no longer detectable
西安电子科技大学 夏玉琼
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Indirect link PK/PD models
CL1e equilibrium clearanceCLe0 transfer clearance
Peripheral compartment
Central compartment
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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Indirect response PK/PD models
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Similar to indirect link PK/PK model the time courses of plasma concentration and effect
are also dissociated resulting in counterclockwise hysteresis for the concentration–effect relationship,
But the reason is a time-consuming indirect response mechanism
西安电子科技大学 夏玉琼
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Indirect response PK/PD modelsA time-consuming indirect response
Dynamic equilibrium
西安电子科技大学 夏玉琼
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Indirect response PK/PD models
Model predicted and observed plasma concentration (observed: circles; predicted: solid line) and eosinophil count (observed, squares; predicted, dashed line) following SC administration of 1 mg/kg of the anti-IL-5 humanized monoclonal antibody SB-240563 in a Cynomolgus monkey
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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Cell lifespan models
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Apply to the proteins that exert their pharmacologic effect through direct or indirect
modulation of blood and/or immune cell types Established based on the sequential maturation and lifespan-driven cell turnover
of their affected cell types and progenitor cell populations Especially widely used for characterizing the dose–concentration–effect relationships
of hematopoietic growth factors aimed at modifying erythropoiesis, granulopoiesis, or thrombopoiesis
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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45 Con
cent
ratio
n in
pla
smaC
ount
s of
RBC
Retic
uloc
ytes
(网
状细
胞)
Solid and open circles data for males and females
Solid and broken lines model fittings
After multiple SC dosing of 600 IU/kg/week recombinant human erythropoietin
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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*Complex response modelsIndirect response model
Indirect link model
西安电子科技大学 夏玉琼
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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
西安电子科技大学 夏玉琼
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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.
西安电子科技大学 夏玉琼