Proteins and Peptides

1. PHARMACOKINETICS AND
PHARMACODYNAMICS OF PROTIENS
AND PEPTIDES
PRESENTED BY: SACHINKUMAR BHAIRAGOND
1st Year M. PHARMA
DEPT OF PHARMACEUTICS
SRINIVAS COLLEGE OF PHARMACY1

2. CONTENTS
1. Introduction of Proteins and Peptides
2. Pharmacokinetics:
a) Administration Pathways-
-Administration by Injection or Infusion
-Inhalation Administration
-Transdermal Administration
b) Distribution
c) Elimination
3. Pharmacodynamics
4. Conclusion
5. References 2

3. PROTIENS AND PEPTIDES
INTRODUCTION
• Protein :- Protein are the large organic compounds made up of amino acids
arranged in a linear chain attached by a peptide chain.
Protein > 50 amino acids
• Peptide :- These are the short polymers formed from the linking, in a defined
order of amino acids.
Peptide < 50 amino acids
• The protein and peptides are important in biological cells. Our body requires
many proteins for development of organs and maintaining circadian rhythm. 3

4. • The small numbers of peptide and protein-based therapeutics have long been used
in medical practice (e. g., calcitonin or glucagon).
• Recombinant human insulin, which was approved in 1982, was the first of these
biotechnologically derived drug products, and many more have followed during
the past 25 years.
• The study of Pharmacokinetics and Pharmacodynamics of proteins and peptides,
Pharmacokinetics is “What the Body does to the Drug”.
Pharmacodynamics is “What the Drug does to the Body”.
4

5. Pharmacokinetics:- Administration Pathways
• Peptides and proteins, unlike conventional small-molecule drugs, are generally not
therapeutically active upon oral administration.
• The lack of systemic bioavailability is mainly caused by two factors: high
gastrointestinal enzyme activity, and low permeability through the gastrointestinal
mucosa. 5

6. • The substantial peptidase and protease activity in the gastrointestinal tract makes it
the most efficient body compartment for peptide and protein metabolism &
gastrointestinal mucosa presents a major absorption barrier for water soluble
macromolecules such as peptides and proteins.
• Due to the lack of activity after oral administration for most peptides and proteins,
administration by injection or infusion – that is, by intravenous (IV), subcutaneous
(SC), or intramuscular (IM) administration – is frequently the preferred route of
delivery for these drug products.
6

7. Administration by Injection or Infusion
• Injectable administration of peptides and proteins offers the advantage by
overcoming presystolic degradation, thereby achieving the highest concentration in
the biological system.
• Examples of FDA-approved proteins given by the IV route include the tissue
plasminogen activator (t-PA) analogues alteplase , the recombinant human
erythropoietin epoetin – α .
7

8. • IV administration as either a bolus dose or constant rate infusion may not always
provide the desired concentration– time profile depending on the biological activity
of the product, and IM or SC injections may be more appropriate alternatives.
• For example, luteinizing hormone releasing hormone (LH-RH) in bursts stimulates
the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH),
whereas a continuous baseline level will suppress the release of these hormones
8

9. Pharmacokinetic parameters of select FDA-approved protein/peptide drugs as reported in the
prescribing information.
9

10. (Continued)
10

11. Inhalational Administration
• Inhalational delivery of peptides and proteins offers the advantage of ease of
administration, the presence of a large surface area available for absorption, high
vascularity of the administration site, and bypass of hepatic first pass metabolism.
• Disadvantages of inhalation delivery include the presence of certain proteases in the
lung, potential local side effects of the inhaled agents on the lung tissues ( i.e.,
growth factors and cytokines), and molecular weight limitations.
11

12. • The success of inhaled peptide and protein drugs can be exemplified by inhaled
recombinant human insulin products, with Exubera being the first approved
product (2006), and several others in clinical development.
• Inhaled insulin offers the advantages of ease of administration and rapid onset with
a shorter duration of action for tighter postprandial glucose control as compared to
subcutaneously administered regular insulin.
• Dornase-α , which is indicated for the treatment of cystic fibrosis, is another
example of a protein drug successfully administered through the inhalation route.
12

13. Transdermal Administration
• Transdermal drug delivery offers the advantages of bypassing metabolic and
chemical degradation in the gastrointestinal tract, as well as first-pass
metabolism by the liver.
• Methods frequently used to facilitate transdermal delivery include sonophoresis
and iontophoresis. Both methodologies increase skin permeability to ionic
compounds. Therapeutic doses of insulin, interferon-γ, and epoetin-α have all
been successfully delivered transdermally via sonophoresis
13

14. Distribution
• Whole-body distribution studies are essential for classical small-molecule drugs in
order to exclude any tissue accumulation of potentially toxic metabolites.
• This problem does not exist for protein drugs, where the catabolic degradation
products (amino acids) are recycled in the endogenous amino acid pool.
• Therefore, biodistribution studies for peptides and proteins are performed primarily
to assess targeting to specific tissues as well as to identify the major elimination
organs.
• The volume of distribution of a peptide or protein drug is determined largely by its
physio-chemical properties (e.g., charge, lipophilicity), protein binding, and
dependency on active transport processes. 14

15. • After IV application, peptides and proteins usually follow a biexponential plasma
concentration–time profile that can best be described by a two-compartment
pharmacokinetic model.
• The central compartment in this model represents primarily the vascular space and
the interstitial space of well-perfused organs with permeable capillary walls,
especially liver and kidneys, while the peripheral compartment comprises the
interstitial space of poorly perfused tissues such as skin and (inactive) muscle.
• Active tissue uptake can substantially increase the volume of distribution of peptide
and protein drugs, as for example observed with atrial natriuretic peptide (ANP).
15

16. • Another factor that can influence the distribution of therapeutic peptides and proteins
is binding to endogenous protein structures. Physiologically active endogenous
peptides and proteins frequently interact with specific binding proteins involved in
their transport and regulation. Ex :- growth hormone
• Protein binding not only affects whether the peptide or protein drug will exert any
pharmacological activity, but on many occasions it may also have an inhibitory or
stimulatory effect on the biological activity of the agent.
E.g. :-Recombinant cytokines.
16

17. Elimination
• In general, peptides and protein drugs are almost exclusively eliminated by
metabolism via the same catabolic pathways as endogenous or dietary proteins,
resulting in amino acids that are reutilized in the endogenous amino acid pool for de-
novo biosynthesis of structural or functional body proteins.
17

18. Elimination
• Proteolysis :- Proteolytic enzymes such as proteases and peptidases are ubiquitous
throughout the body. As proteases and peptidases are also located within cells,
intracellular uptake is seen more an elimination rather than a distribution process.
• Gastrointestinal :- For orally administered peptides and proteins, the
gastrointestinal tract is the major site of metabolism. Presystolic metabolism is the
primary reason. Parenterally administered peptides and proteins may also be
metabolized in the intestinal mucosa following intestinal secretion.
18

19. • Hepatic :- the liver may also contribute substantially to the metabolism of peptide and
protein drugs. Proteolysis usually starts with endopeptidases that attack in the middle
part of the protein, and the resulting oligopeptides are then further degraded by
exopeptidases.
• The ultimate metabolites of proteins, amino acids and dipeptides, are finally reutilized
in the endogenous amino acid pool. The rate of hepatic metabolism is largely
dependent on specific amino acid sequences in the protein.
19

20. • Renal :- Renal metabolism of peptides and small proteins is mediated through three
highly effective processes.
1. The first mechanism involves the glomerular filtration of larger, complex peptides
and proteins, followed by reabsorption into endocytic vesicles in the proximal
tubule and subsequent hydrolysis into small peptide fragments and AA.
2. The second mechanism entails glomerular filtration followed by intra luminal
metabolism, predominantly by exopeptidases in the luminal brush border
membrane of the proximal tubules.
20

21. 3. The third mechanism is peritubular extraction of peptides and proteins from post
glomerular capillaries and intracellular metabolism.
The determining factors for clearance of protein and peptide include molecular
weight as well as a molecule’s physio-chemical properties, including size, overall
charge, lipophilicity, functional groups, secondary and tertiary structure.
21

22. 22

23. PHARMACODYNAMICS
• Pharmacodynamics refers to the relationship between the drug concentration at
the site of action (receptor) and pharmacologic response, including
biochemical and physiologic effects that influence the interaction of drug with
the receptor.
• The interaction of the drug molecule with a receptor causes the irritation of a
sequence of molecular events resulting in a pharmacologic or toxic response.
• Pharmacokinetic-pharmacodynamic models are constructed to relate plasma
drug level to drug concentrated in the site of action and establish the intensity
and time course of the drug.
23

24. Receptor-Mediated Endocytosis
• For conventional small-molecule drugs, receptor binding is usually negligible
compared to the total amount of drug in the body, and rarely affects their
pharmacokinetic profile.
• In contrast, a substantial fraction of a peptide and protein dose can be bound to
receptors. This binding can lead to elimination through receptor mediated
uptake and subsequent intracellular metabolism.
• The endocytosis process is not limited to hepatocytes, but can also occur in
other cells, including the therapeutic target cells.
24

25. • The binding and subsequent degradation via interaction with these generally
high-affinity, low-capacity binding sites is a typical example for a
pharmacologic target-mediated drug disposition, where binding to the
pharmacodynamic target structure affects drug disposition.
• Since the number of receptors is limited, drug binding and uptake can usually
be saturated within therapeutic concentrations, or more specifically at
relatively low molar ratios between the protein drug and the receptor.
• As a consequence, the pharmacokinetics of these drugs frequently does not
follow the rule of superposition, i.e., clearance, and potentially other
pharmacokinetic parameters are dose-dependent.
25

26. • Thus, receptor-mediated elimination constitutes a major source for the nonlinear
pharmacokinetic behavior of numerous peptide and protein drugs, resulting in a lack of
dose proportionality
Conclusion
• Peptide and protein drugs are subject to the same general principles of pharmacokinetics
and exposure–response correlations as conventional small-molecule drugs. Due to their
similarity to protein nutrients and/or especially regulatory endogenous peptides and
proteins.
• pharmacokinetic/pharmacodynamic correlations are frequently complicated due to the
close interaction of peptide and protein drugs with endogenous substances and receptors,
as well as regulatory feedback mechanisms.
26

27. References
1. Meibohm.B. Pharmacokinetics and pharmacodynamics of biotech drugs,
WILEY-VCH, Germany;2006:17-37.
27

28. THANK YOU
28