By YuqiongXia 3/17/2016 - web.xidian.edu.cnweb.xidian.edu.cn/yqxia/files/20160317_222706.pdfPharmacodynamics 6 Drug effect or toxicity, usually at the assumed site of drug action “what

By Yuqiong Xia3/17/2016

Pharmacokinetics and pharmacodynamics

Pharmaceutical Biotechnology 西安电子科技大学夏玉琼

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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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 pre-systematic 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 cells


Outline

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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


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


Less important way from vascular to interstitial

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transcellular migration via endocytosis

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


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


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Effect of protein (Ab) binding on distribution西安电子科技大学夏玉琼

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


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 西安电子科技大学夏玉琼

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


Pathways of renal metabolism of peptides and proteins

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Either (a) intraluminal metabolism or (b) tubular reabsorption and (c) peritubular excretion


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


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

1. preventing the protein from being recognized by the immune system 2. reducing its elimination via glomerular filtration or proteolytic enzymes


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 C: drug concentration in plasma

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

Q: distribution clearance

clearance

dose


Outline

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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


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Indirect link PK/PD models

CL1e equilibrium clearanceCLe0 transfer clearance

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 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


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Indirect response PK/PD modelsA time-consuming indirect response

Dynamic equilibrium


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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


Outline

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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


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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


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


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

By YuqiongXia 3/17/2016 - web.xidian.edu.cnweb.xidian.edu.cn/yqxia/files/20160317_222706.pdfPharmacodynamics 6 Drug effect or toxicity, usually at the assumed site of drug action “what