Pharmacokinetics and pharmacodynamics of peptide and protein drugs

Transcription

1 Pharmaceutical Biotechnology Pharmacokinetics and pharmacodynamics of peptide and protein drugs By Yuqiong Xia

2 The dose-concentration-effect relationship 2

3 Pharmacokinetics 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 3

4 Pharmacodynamics 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 4

5 Outline Pharmacokinetics of protein therapeutics absorption of protein therapeutics distribution of protein therapeutics elimination of protein therapeutics Other related issues Pharmacodynamics of protein therapeutics 5

6 Half-life The in vivo disposition 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 6

7 Outline Pharmacokinetics of protein therapeutics absorption of protein therapeutics distribution of protein therapeutics elimination of protein therapeutics Other related issues Pharmacodynamics of protein therapeutics 7

8 Enteral( 肠内的 ) administration 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 8

9 Parenteral( 注射的 ) administration Major routes Intravenous IV 静脉注射 Subcutaneous SC 皮下注射 Intramuscular IM 肌内注射 9

10 The advantages of IV administration 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 10

11 IM and SC administration IV IM and SC Half-time long longer Pre-systemic degradation no yes k a absorption rate constant k app the apparent absorption rate constant, including systemic circulation and pre-systemic degradation F the bioavailability compared to IV administration 11

12 SC administration 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 12

13 Outline Pharmacokinetics of protein therapeutics absorption of protein therapeutics distribution of protein therapeutics elimination of protein therapeutics Other related issues Pharmacodynamics of protein therapeutics 13

14 Distribution mechanisms and volumes 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 14

15 Protein transport from vascular to tissues Convection: arises from hydrostatic pressure gradient, is always directed across arterial wall from inside to out 15

16 Protein transport from vascular to tissues Endocytosis 16

17 Biodistribution studies Using radioactive label If proteins have tyrosine or lysine, an external label 125 I can be chemically coupled to proteins 17

18 Protein binding of protein therapeutics 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 18

19 Distribution via receptor-mediated uptake 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 19

20 Outline Pharmacokinetics of protein therapeutics absorption of protein therapeutics distribution of protein therapeutics elimination of protein therapeutics Other related issues Pharmacodynamics of protein therapeutics 20

21 Proteolysis Degradation from proteins to peptides, from peptides to amino acids MW determines the major metabolism site and predominant degradation process 21

22 Gastrointestinal protein metabolism 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 22

23 Renal protein metabolism and excretion Major route for small proteins (<=60 kd) Undergo glomerular filtration, most efficient for proteins <= 30 kd 23 =62326&resid=121571

24 Hepatic protein metabolism Major route Small proteins and peptides Simple diffusion or a carrier-mediated transport Metabolized by microsomal enzymes or cytosolic peptidases 24

25 Hepatic protein metabolism 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 25

26 Receptor-mediated protein metabolism 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 26

27 Outline Pharmacokinetics of protein therapeutics absorption of protein therapeutics distribution of protein therapeutics elimination of protein therapeutics Other related issues Pharmacodynamics of protein therapeutics 27

28 Target-mediated drug disposition 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 28

29 immunogenicity and protein pharmacokinetics CL: clearance 29

30 Chemical modifications for optimizing the pharmacokinetics of protein therapeutics 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 30

31 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 31

32 Pharmacodynamics of protein therapeutics Pharmacodynamics Concentration-effect relationship PK/PD modeling integrated pharmacodynamics-pharmacodynamics modeling Dose-exposure-response Widely used in protein therapeutics 32 Make predictions of drug effects under new conditions

33 33 Direct link PK/PD models 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

34 Direct link PK/PD models 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 link PK/PD models Temporal disassociation between plasma concentrations and effect Plasma concentration maxima occur before effect maxima 36

37 Indirect link PK/PD models CL 1e equibrium clearance CL e0 transfer clearance 37

38 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 38

39 Indirect response PK/PD models 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 39

40 Indirect response PK/PD models 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 Cell span models 红色祖细胞成红血球细胞网状红细胞红细胞 42

43 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 43

44 Complex response models Indirect response model 44 Indirect link model

45 Homework 5 Tell the differences between pharmacokinetics and pharmacodynamics. Give at least three ways to eliminate protein therapeutics from the body. 45