Microsoft PowerPoint - 5 Pharmacokinetics and pharmacodynamics of peptide and protein drugs

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1 Pharmaceutical Biotechnology Pharmacokinetics and pharmacodynamics By Yuqiong Xia 2014

2 Keywords Pharmacokinetics, pharmacodynamics, dose Metabolism, excretion Lymphatic, vascular, renal, hepatic, bile, lysosome 2

3 The dose-concentration-effect relationship 3

4 4

5 Pharmacokinetics Change in the concentration of a drug in plasma or blood) Serum concentration time Include drug absorption, distribution, metabolism and excretion what the body does to the drug 5

6 Pharmacodynamics Drug effect or toxicity, usually at the assumed site of drug action what the drug does to the body 6

7 Outline Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization Pharmacodynamics of protein therapeutics 7

8 Half-life The half-life of peptide and protein drugs may often be predicted from their physiological function Peptides or proteins Peptides having hormone activity insulin Albumin having transport task Immunoglobulin Elimination half-life Very short 26 min at 1 U/kg Several days Several days 8

conjugations Coadministration of protease inhibitors 9 http://www.

9 Oral administration To overcome the low bioavailability of oral route Encapsulating drugs in micro- or nanoparticles Chemical modifications and conjugations Coadministration of protease inhibitors 9

10 10

11 IV administration No presystematic degradation Achieve the highest concentration in the biological system A bolus dose Short half-life 11

12 IM and SC administration Pre-systematic degradation Lower bioavailability Longer half-life 12

13 SC administration Blood capillaries or lymphatic vessels Macromolecules(>16 kda) are predominantly absorbed into lymphatics Efficient in targeting lymphoid cells 13

14 Outline Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization Pharmacodynamics of protein therapeutics 14

15 Distribution volume Generally, limited to extracellular space Sometimes larger Active tissue uptake Bind to intra- or extravascular proteins Positive proteins bind to negative membrane stronger 15

16 From vascular space to interstitial space Convection: due to the hydrostatic pressure gradient Convection brings drug from vessel to tissue Lymph drainage remove drug from tissue 16

17 From vascular space to interstitial space Endocytosis 17

18 Effect of Protein binding on distribution Affects the fraction of a drug available to exert pharmacological activity Prolongs protein circulation time Enhances protein clearance 18

19 Effect of protein (Ab) binding on distribution 19

20 生物制药工程 Effect of receptor-mediated uptake on 西安电子科技大学 distribution Result in therapeutically effective tissue concentrations, but a relatively small volume of distribution 夏玉琼 Tissue Receptor Drug Vessel 20

21 Outline Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization Pharmacodynamics of protein therapeutics 21

22 Proteolysis Degradation from proteins to peptides, from peptides to amino acids 22

23 Proteolysis depends on MW 23

Gastrointestinal protein metabolism Major site, due to high proteolytic enzyme activity Mostly for orally administrated drugs Parental drugs

24 Gastrointestinal protein metabolism 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 24

25 Renal protein metabolism and excretion Major route for small proteins (<=60 kd) Undergo glomerular filtration, most efficient for proteins <= 30 kd 25 &resid=121571

Hepatic protein metabolism 26 Major route Protein enter cytosol by diffusion, metabolized by microsomal enzymes( 微粒体酶 ) Protein enter by carrier

26 Hepatic protein metabolism 26 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 lysome

27 Outline Pharmacokinetics of protein therapeutics Absorption Distribution Elimination Chemical modifications for optimization Pharmacodynamics of protein therapeutics 27

Chemical modifications Delete, add or replace

28 Chemical modifications Delete, add or replace amino acids Glycosylation Conjugate to polymer

29 Outline 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 29

30 PK/PD modeling Simulate time course of effect of a drug 30

Peripheral compartment E max : maximum achievable effect EC 50 :

31 Direct link PK/PD models The relationship between concentration in plasma and in effect site is constant Central compartment Clearance Peripheral compartment E max : maximum achievable effect EC 50 : concentration of the drug that produced half of the maximum effect n: Hill coefficient 31

32 Outline 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 32

33 Indirect link PK/PD models There is a delay between concentrations in plasma and the effect site Central compartment Peripheral compartment CL 1e equibrium clearance CL e0 transfer clearance 33

34 Indirect link PK/PD models There is a delay between concentrations in plasma and the effect site Concentration in plasma Concentration in effect site 34

35 Outline 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 35

36 Indirect response PK/PD models A time-consuming indirect response 36

37 Outline 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 37

38 Process of erythropoiesis( 红细胞生成 ) 多能干细胞白细胞血小板红细胞祖细胞爆炸红系集落形成单位红系集落形成单位祖细胞 1 红细胞前体红细胞网状红细胞祖细胞 2 红细胞 38

39 生物制药工程夏玉琼 Cell lifespan models of rhepo( 重组促红细胞生成素西安电子科技大学 ) 祖细胞 1 祖细胞 2 网状红细胞 Stimulation 红细胞 Inhibition 39

40 Concentrationinplasma CountsofRBC Reticulocytes( 网状细胞 ) 40

41 Outline 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 41

42 Complex response models Indirect response model 42 Indirect link model

43 Summary 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 43

44 Homework 4 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. 44

rate extent (2-3) 40-50 physiological availability systematic availability bio-phase availability biological availability bioavailability 1977 FDA Bio

rate extent (2-3) 40-50 physiological availability systematic availability bio-phase availability biological availability bioavailability 1977 FDA Bio Drug Bioavailability and Therapeutic Effects 1. efficacy2. safety3. applicability4. uniformity (1) E = k 1 f (A, C, S) E A C S k 1 A E = k 2 f (C, S) k 2 ( ) bioavailability 191 rate extent (2-3) 40-50