Pharmacokinetics and pharmacodynamics of biotechnology drugs. Introduction, Proteins and peptides, Monoclonal antibodies, Oligonucleotides, Vaccines (immunotherapy), Genetherapies

1. PHARMACOKINETICS AND PHARMACODYNAMICS OF
BIOTECHNOLOGY DRUGS. INTRODUCTION, PROTEINS AND
PEPTIDES, MONOCLONAL ANTIBODIES, OLIGONUCLEOTIDES,
VACCINES (IMMUNOTHERAPY), GENETHERAPIES
Prepared by,
Ravi Kotadiya
M.Pharm sem 2
SDPC, Surat.
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2. CONTENT
• Introduction
• Protein and peptides
• Monoclonal antibodies
• Oligonucleotides
• Vaccines (immunotherapy)
• Gene therapies
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3. INTRODUCTION
• Cellular biology and in biotechnology allowed to create new therapeutic
entities mimicking endogenous bioactive substances.
• The use of biological materials to create a specific drug product, has
become an important sector of the pharmaceutical industry and accounts
for the fastest-growing class of new drugs in the market.
• These new products used against microbiological, non-microbiological
and gene therapy treatment.
• Their pharmacokinetics and P’codynamics properties needs to
understand.
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4. PROTEIN AND PEPTIDES
• Protein : Protein are the large organic compound made of amino acids
arranged in linear chain and joined together by peptide bonds.
Protein > 50 amino acids
Molecular weight above 5000
• Peptide : These are short polymer formed from the linking in a defined
order of amino acids
Peptide < 50 amino acids
Molecular weight less than 5000
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5. PHARMACOKINETICS
Administration:
• Protein and peptides are not active in oral dose. Except small molecular weight
peptides like desmopressin.
• They are given through IV bolus or infusion, Intramuscular or dermal route.
• Volume of distribution (Vd) is small and roughly inversely proportional to their
molecular weight. Vd at steady state is not more than twice the initial Vd.
Elimination:
• It depends on charge, oil/water partition coefficient, the presence of sugars or other
functional groups and molecular weight.
• Small protein filtered by glomerulus in the kidney.
• Proteins are degraded in livery by cellular catabolism.
• Larger protein eliminated by phagocytosis.
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6. MONOCLONAL ANTIBODIES
• It is immunoglobulin or protein molecule
produced by recombinant DNA technology.
• It has high purity and all antibodies are identical
in structure.
• Monoclonal antibodies can also target and
deliver toxin specifically to cancer cells and
destroy them while sparing normal cells and
important detectors used in laboratory
diagnostics.
• Huge number of antibody can produced by
body if foreign substance containing antigenic
site are present.
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7. PHARMACOKINETICS
Absorption:
• Most mAbs are given by IV route but other vascular routes like subcutaneous and
intramuscular route are also preferable.
• Oral route shows very little bioavailability and it transported by receptor mediated
transcellular and paracellular route.
Distribution:
• It shows small volume of distribution.
Elimination:
• Renal excretion is very low for mAbs.
• It can not filtered by glomerular filtration.
• mAbs bind to Fab region of antigen of the cell and it is irreversible, subsequently
it is internalized and degrade by the cell.
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8. PHARMACODYNAMICS
• Three different pharmacodynamic principles can be distinguished for mAbs,
1. Lysis or apoptotic activity,
2. Coating activity,
3. Inactivating activity,
depending on the type of antigen and the antigen–antibody interaction.
• In the first two cases, the disease-specific antigen is located on the surface of a cell.
The majority of mAbs exert their pharmacodynamic activity by Fc-mediated ADCC/
CDC activation or delivery of toxic substance to the targeted cell . Cell death will be
the ultimate result.
• In last case are directed against soluble substances as antigens. The
pharmacodynamic principle is to block the antigen-binding activity to its receptor and
thereby inactivate the target antigen function. The binding of the therapeutic antibody
to the target antigen finally leads to agglutination and neutralization of the antigen.
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9. OLIGONUCLEOTIDES
• These are single stranded short DNA or RNA sequence also known as antisense
drug.
• It blocks DNA or RNS transcription and translation to moderate disease processes.
• It is designed to target specific DNA or RNA to block the sequence of particular
protein.
• Oligonucleotides are synthesized by phosphoramitide.
• It is used to target virus and cancer cells of the body.
• It blocks the production of protein necessary for viral replication.
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10. PHARMACOKINETICS
Absorption:
• It is mostly administered through intravenous, intraperitoneal or subcutaneous route.
• A plasma concentration–time profile that is poly-phasic with rapid distribution half-life
(1 h) and long elimination half-life reflecting slow elimination from the tissues.
• Long tissue elimination cleared by nuclease mediated metabolism.
Distribution:
• It is mostly found in every tissue except brain.
• Liver and kidney shows highest concentration.
Elimination:
• It is primarily metabolized in tissue in small fragments and excreted by urine form the
body.
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11. VACCINES (IMMUNOTHERAPY)
• A vaccine is a biological preparations that improves immunity to a particular
disease.
• A vaccine typically contains an agent that resembles a disease causing
microorganism and is often made from weakened or killed forms of the microbe, its
toxins or one of its surface proteins.
• Vaccines are dead or inactivated organisms or purified product derived from them.
The different types of vaccines are :
a) Traditional vaccines
b) Innovative vaccines
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12. A) TRADITIONAL VACCINES
1. Killed : Some vaccines contain killed, but previously virulent, microorganism that
have been destroyed with chemicals, heat, radioactivity or antibiotics.
Examples : are influenza, cholera, polio, hepatitis A, and rabies.
2. Live, attenuated : Some vaccines contain live, attenuated microorganisms. Many
of these are active viruses that have been cultivated under conditions that
disable their virulent properties or that use closely related but less dangerous
organisms to produce a broad immune response.
Example : are yellow fever, measles, mumps.
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13. 3. Toxoid : Toxoid vaccines are made from inactivated toxic compound
that cause illness rather than the microorganism.
Examples : are Tetanus and Diphtheria.
4. Subunit : Protein subunit – Rather than introducing an inactivated or
attenuated microorganism to an immune system (which would
constitute a whole agent vaccine), a fragment of it can create an
Immune response.
Example : Meningococcal disease and Pneumococcal disease.
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14. B) INNOVATIVE VACCINES
1. Conjugate vaccines - Certain bacteria have polysaccharide outer coats that are
poorly immunogenic. By linking these outer coats to protein(e.g. toxin), the
immune system can be led to recognize the polysaccharide as if it were a
protein antigen.
Example : Hib (Haemophilus influenza type b) disease
2. Recombinant vector vaccine - By combining the physiology of one
microorganism and the DNA of the other, immunity can be created against
diseases that have complex infection process.
Example : Hepatitis B
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15. 3. T-cell receptor peptide vaccine : They show the modulation of cytokine
production and improve cell mediated immunity and are under development.
Use : to stimulate antitumor T cell
4. Valence :
a) Monovalent- Use to immunize against single antigen.
b) Multivalent- Used to immunize against two or more microorganism.
Uses : Hepatitis A, Hepatitis B, mumps, rubella, diphtheria, chickenpox etc
5. Heterotypic : Vaccines that are pathogens of other animals that either do not
cause disease or cause mild disease in the organism being treated.
Use : diphtheria
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16. GENE THERAPY
• Gene therapy refers to deliver recombinant gene to somatic cells in vivo which
produce protein that have therapeutic benefits to the patient.
• Therapeutic approach is restoration of defective biological function of the cell.
• To deliver gene into cell different approaches have been used.
1. Virus based approach:
• It involves replacing viral replicative genes with the transgene, then packaging the
rDNA into the viral particle.
• These virus can infect target cells and express transgene.
• Both retroviruses, RNA viruses that have the ability to permanently insert their
genes into the chromosomes of the host cells.
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17. 2. Non virus based approach:
• It also have some success in in-vivo gene delivery.
• The transgene is engineered into a plasmid vector, which contains gene-expression
control regions.
• This naked DNA delivery technique is being tested as possible DNA vaccines, in
which the muscle cells produce small amounts of antigen that stimulate immunity to
the antigen.
3. Cell based approach:
• It involves the administration of transgenes to cells that have been removed from a
patient.
• Cells are removed from the patient; genes encoding a therapeutic product are then
introduced into these cells ex vivo using a viral or non-viral delivery system, and
then the cells are returned into the patient.
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