5 Pharmacokinetics and pharmacodynamics of peptide and ...web.xidian.edu.cn/yqxia/files/20131201_222824.pdf · Pharmacokinetics 3 The time course of the concentration of a drug in

By Yuqiong Xia2013-10-12

Pharmacokinetics and pharmacodynamics of peptide and protein drugs

Pharmaceutical Biotechnology

2

The dose-concentration-effect relationship

生物制药工程夏玉琼西安电子科技大学

Pharmacokinetics

3

The time course of the concentration of a drug in a body fluid, preferably plasma or blood

Comprises all processes affecting drug absorption, distribution, metabolism and excretion

“what the body does to the drug”


Pharmacodynamics

4

The intensity of a drug effect or toxicity resulting from certain drug concentrations in a body fluid, usually at the assumed site of drug action

“what the drug does to the body”


Outline

5

Pharmacokinetics of protein therapeutics absorption of protein therapeutics distribution of protein therapeutics elimination of protein therapeutics Other related issues

Pharmacodynamics of protein therapeutics


Half-life

6

The in vivo disposition 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


Outline

7




Enteral(肠内的) administration

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Same as “oral administration” Oral administration has low bioavailability High gastrointestinal enzyme activity Low permeability through the gastrointestinal mucosa

Strategies to overcome the obstacles Encapsulating drugs in micro- or nanoparticles Chemical modifications and conjugations to improve the

resistance to degradation and the permeability of the protein drug

Coadministration of protease inhibitors生物制药工程夏玉琼

西安电子科技大学

Parenteral（注射的） administration

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Major routes Intravenous IV静脉注射

Subcutaneous SC皮下注射

Intramuscular IM肌内注射


The advantages of IV administration

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Circumvent (绕过) pre-systemic degradation Achieve the highest concentration in the biological

system Examples The tissue plasminogen activator analogs alteplase and

tenecteplase 组织血纤维蛋白溶酶原激活子类似物 The recombinant human erythropoietin （红细胞生成素）

epoetin-α The granulocyte-colony-stimulating factor filgrastim 有粒

细胞菌落刺激因子


IM and SC administration

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IV IM and SCHalf-time long longerPre-systemic degradation no yes

ka absorption rate constantkapp the apparent absorption rate constant,including systemic circulation and pre-systemic degradationF the bioavailability compared to IV administration


SC administration

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Peptides and protein therapeutics may enter the systemic circulation either via blood capillaries or through lymphatic vessels

Macromolecules larger than 16 kDa are predominantly absorbed into lymphatics

Especially efficient when drugs need to target lymphoid cells


Outline

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Distribution mechanisms and volumes

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Most proteins have high MW and large sizes, and distribution volumes are volume of extracellular space

Some proteins can specially bind to intra- or extravascular proteins, and distribution volumes are larger

Positively charged proteins can bind to negatively charged membrane easily, and distribution volumes are larger


Protein transport from vascular to tissues

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Convection: arises from hydrostatic pressure gradient, is always directed across arterial wall from inside to out

http://ajpheart.physiology.org/content/275/6/H2236


Protein transport from vascular to tissues

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Endocytosis

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


Biodistribution studies

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Using radioactive label If proteins have tyrosine or lysine, an external label

125I can be chemically coupled to proteins

http://shiyan.ebioe.com/11681.htm


Protein binding of protein therapeutics

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Only the free unbounded fraction of a drug substance is accessible to distribution and elimination processes as well as interaction with target sites Specific binding Non-specific binding


Distribution via receptor-mediated uptake

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Low volume of distribution should not necessarily lead to low tissue penetration Since receptor-mediated uptake has low volume of

distribution but therapeutically effective tissue concentration


Outline

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Proteolysis

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Degradation from proteins to peptides, from peptides to amino acids

MW determines the major metabolism site and predominant degradation process


Gastrointestinal protein metabolism

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Gastrointestinal tract is a major site, due to high proteolytic enzyme activity

Not just orally administrated drugs Parental drugs can be metabolized in the intestinal

mucosa following intestinal excretion


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 Small proteins and peptides Simple diffusion or a carrier-mediated transport Metabolized by microsomal enzymes or cytosolic

peptidases

http://www.nfgbw.com/up_files/0111.jpg


Hepatic protein metabolism

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Larger peptides and proteins Carrier-mediated, energy-dependent endocytosis The endocytotic vehicles fuse with or

mature into lysomes

Direct transcytotic pathway Endocytotic vesicle fuse with bile

canalicular membrane and release its

contents by exocytosis into bile


Receptor-mediated protein metabolism

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Not limited to a specific organ or tissue type Protein therapeutics bind with high affinity to

receptors on cell surface Then receptor-mediated uptake by endocytosis Subsequent intracellular lysosomal metabolsim


Outline

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Target-mediated drug disposition

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Protein therapeutics bind to targets Target is capacity-limited and saturable With increasing dose levels, the mean-life of drugs

will increase and the clearance will decrease Over-proportional increase in systemic exposure


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immunogenicity and protein pharmacokinetics

CL: clearance


Chemical modifications for optimizing the pharmacokinetics of protein therapeutics

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Addition, deletion or exchange of selected amino acids within the protein’s sequence

Glycosylation or deglycosylation Covalent linkage to polymers PEGylation prevents proteins from being recorgnizied

by the immune system and reduce its elimination


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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Pharmacodynamics Concentration-effect relationship

PK/PD modeling integrated pharmacodynamics-pharmacodynamics

modeling Dose-exposure-response Widely used in protein therapeutics Make predictions of drug effects under new

conditions生物制药工程夏玉琼


Direct link PK/PD models

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Concentration: in plasma Response: concentration in its effect site If the relationship between the two concentrations

is constant without delay, then direct link PK/PD model can serve

Emax maximum achievable effect,

C drug concentration in plasma,

EC50 the concentration of the drug that

produces half of the maximum effect.

n shape factor生物制药工程夏玉琼


34

Direct link PK/PD models


Outline

35



Indirect link PK/PD models

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Temporal disassociation between plasma concentrations and effect

Plasma concentration maxima occur before effect maxima


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Indirect link PK/PD models

CL1e equibrium clearanceCLe0 transfer clearance


Outline

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Indirect response PK/PD models

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Drug concentration at the effect site and response systems are not direct, but have a delay

Representative response parameter via dynamic equilibrium between increase and decrease of the response


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Indirect response PK/PD models


Outline

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42

Cell span models

红色祖细胞

成红血球细胞

网状红细胞

红细胞


Outline

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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

Homework 5

45

Tell the differences between pharmacokinetics and pharmacodynamics.

Give at least three ways to eliminate protein therapeutics from the body.


Documents

5 Pharmacokinetics and pharmacodynamics of peptide and ...web.xidian.edu.cn/yqxia/files/20131201_222824.pdf · Pharmacokinetics 3 The time course of the concentration of a drug in