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Pharmacokinetics and Pharmacodynamics of
Biotechnology Drugs along with its applications
(Proteins and Peptides, Monoclonal antibodies,
Oligonucleotides, Gene therapy, Vaccines)
Presented by,
Snehal R. Tidke
M.Pharm 2nd Semister,
Pharmaceutics Department
Biotechnology drugs
The steady advances in cellular biology and
biotechnology have allowed scientist to create new
therapeutic entities mimicing the endogenous bioactive
substances.
These new products include Proteins and
Peptides(PPTs), Monoclonal antibodies(mAbs),
Oligonucleotides, Gene therapy treatment and Vaccines
against microbiological and non microbiological diseases.
PROTEINS AND PEPTIDES
Proteins and Peptides
Naturally occuring large molecules with secondary or
tertiary structure.
Ensures proper functioning of body's biological events.
Potent, less toxic, binds to their target.
Biotechnologically proteins and peptides are developed
rapidly.
Majority of this drugs are administered parenterally either
by subcutaneous, intramuscular or by systemic
intravenous injection or infusion.
P'kinetic and P'dynamic-
Absorption
Inhalation administration
Offers ease of administration, provides large surface area
of absortion, bypass first pass metabolism.
Inhaled protein: DNase (pulmozyme)
Enzyme used to break down mucus secretion in
respiratory tracts of patients with cystic fibrosis.
Exubera- systemic form of human insulin to exert
therapeutic effect in inhaled form.
on administration to lungs in dry powder inhaler,
disposition and efficacy were found to be comparable to
those of s.c adm of insulin and absorption was faster.
Transdermal administration
Offers advantageous route of bypassing metabolic
degradation and chemical degradation in gastro intestinal
tract and first pass metabolism in liver.
Methods used to Facilitate Transdermal drug delivery
system include sonophorosis and iontophorosis as it
increses skin permeability to ionic compounds.
Ex. Insulin, Interferon-ɣ and Epoetin-α
Distribution
Biodistribution studies od PPTs are performed to asses
targeting to specific tissues and to identify major
elimination organs.
The volume if distribution is determined by physio-
chemical properties, protein binding and dependency of
active transport processes.
After i.v application, PPTs usually follow biexpotential
plasma concentration-time profile which is described by
two-compartment p'kinetic model.
Active tissue uptake can increase Vd of PPTs.
Binding to endogeneuos protein structure can influence
the distribution of PPTs.
Elimination
 Proteolysis: Proteases and peptidases enzymes are
located within the cells, intracellular uptake is seen more
in elimination rather than distribution process.
Gastrointestinal: Major site of metabolism for orally
administered PPTs. Presystemic metabolism is primarly
seen. Parenterally administered PPTs metabolised in
intestinal mucosa following intestinal secretion.
Hepatic: Proteolysis usually starts with endopeptidases
that attack in middle part of protein and resulting
oligipeptides are then further degraded by exopeptidases.
Renal
Mediated through three process of mechanism:
1. Involves glomerular filtration of larger complex proteins
and peptides followed by reabsorption into endocytic
vesicles in proximal tubule and hydrolysis into small
fragment .
2. Glomerular filtration is followed by luminal brush border
membrane of proximal tubules.
3. Peritubular extraction of peptides and proteins from post
glomerulatr capillaries and intracellular metabolism.
Examples-
Desmopressin:
Small peptide- 1.18 KDa
Has sufficient bioavailability after intranasal adm to elicit a
systemic therapeutic response.
Used as antidiuretic hormone
Oxytocin:
Peptide with 9 amino acid residues with molecular mass
1.007 KDa.
Given bi i.v infusion
Facilitates childbirth.
Antihaemophilic factor:
Large glycoprotein- 320 KDa
produce by recombinant DNA technology.
Elimination half life-14.6 hrs.
Administration- by intravenous infusion.
Used in treatment of haemophilia.
As short elimination halt life is recorded in i.v studies, several PPTs are given by
s.c or i.m route rather than i.v as delayed absorption causes plasma drug conc.
to remain high for appreciable period of time as shown below-
DRUG Intravenous
route (in hrs)
Subcutaneous
route (time in
hrs)
Intamuscular
route (time
in hrs)
Treatment
Insulin 0.08-0.12 1.5 - Diabetes
Parathyroid
hormone(forteo)
0.083 1.0 - Osteoporosis
Sargramostim 1.0 2.77 - Mylois stimulation
Engraftment(bone marrow
transplant)
Human growth
harmone
0.33-0.5 3.8 4.9 Growth harmone defciency
Interferon α 5.1 - 7 Chronic hepatitis C
The site and mechanism of elimination may be determined
by- charge,oil/water partition coeficient, presence of sugar
or functional group or mol. weight.
ADME differs depending on the size of PPTs as shown in table:
Size of PPTs Molecular weight
(in KDa)
DESCRIPTION
Small proteins <60  Absorption: Proximal tubules (endocytosis)
 lysosomal degradation if complex proteins are present
 metabolised by enzymes in case of v.small linear
peptide ex. bradykinin
Small polypeptide <1 Transportation to hepatocytes for degradation occurs by
• passive diffusion (if lipophilic)
• carrier mediated uptake (if polor)
Moderate size protein 50-200 Receptor mediated endocytosis in liver
Large protein 200-400 In association with immunoglobulins by phagocytosis
MONOCLONAL ANTIBODIES
Monoclonal antibodies (Ig molecule)
Produced by recombinamt DNA technology
Results in molecules being identical in structure and with
high purity.
Most of the clinically developed or approved mAbs are
administered by intravenous infusion.
Produced sufficiently in large quantities for use as
therapeutic agent.
MAbs are humanised to prevent incidence of
hypersensitivity reaction that can occur from antibodies
from foriegn species.
Bexxar and Zevalin are new class of radioimmunotherapy
drugs use to kill cancer cells.
P'kinetic of mAbs
Absorption:
Extra vascular routes have been chosen as alternatives,
including subcutaneous and intramuscular adminstration.
The mAbs enter lymphatic system by convective flow of
interstitial fluid into porous lymphatic vessel and are
further transported unidirectionally into venous system.
 It has been shown that antibodeis can reach systemic
circulation after oral administration, but to very small
extent. The antibodies pass the intestinal epithelium not
by passive transcellular but by receptor mediated
transcellular or paracellular transport.
Distribution
Distribution is poor due to high molecular mass and
hydrophilicity/polarity of the molecules.
Transport:
Permeation across cells/tissues is accomplished by
transcellular or paracellular transport, involving process of
diffusuion, convection and cellular uptake. Due to physio-
chemical properties, extent of diffusion across cell
membrane in transcellular transport is minimal.
Endocytosis is absorptive process of large and polar
molecules involving formation of intracellular vesicles from
parts of cell membranes.
Elimination
Clearance:
As mAbs do not go glomerulatr filtration due to large size,
tubular sectretion has not been reported to occur to any
significant extebnt for mAbs.
Thus renal elimination is uncommon or low for mAb with
exception for low molecular mass mAbs.
Biliary elimination is has been reported for IgA molecules
and only to very small extent.Therefore, total clearance
(CL) does not comprise renal or biliary clearance.
Some of the approved mAb drugs-
DRUG YEAR OF
APPROVAL
ELIMINATION
HALF LIFE
(in hrs)
TARGET APPLICATION
Muromonab 1986 18 CD3 receptor Prevents rejection of
kidney transplant
Abciximab 1994 0.16-0.5
(>10 min)
Inhibits plateplat
aggregation by
targeting
glycoprotein
Prevention of thrombosis
in percutaneuos coronary
intervention
Bevacizumab 2004 20 days Vascular endothelial
groth factor
Colorectal cancer,
Lung cancer,
Metastatic lung cancer
Applications
1. Cancer treatment- mAbs against leukemia and
lymphomas have been used in treatment with variable
results.
2. Imaging diagnosis- mAbs is used with radioactive
markers to locate and visualise location and extent of the
tumors.
3. Target specific delivery- mAbs used along with
liposomes. Ex. prokinase congugate with mAbs to
disslove fibrin clots.
4. Transplant rejection suppression- In kidney transplant,
mAbs against CD3 is used.CD3 causes rejection
OLIGONUCLEOTIDES
Therapeutic Oliginucleotides are short strands of
nucleotides that interfere with pathogenic proteins.
Oligonucleotides showing activity can serve as basis for
product of MAb or other component that may be eaily
approved for clinical use.
Only two oligoneucleotides have been approved for
clinical use-
1. Fomvirsen - FDA approval in 1998
2. Pegaptanib - FDA approval in 2004
PHARMACOKINETICS: Absorption-
Antisense oligonucleotides are majorly administered
parenterally as reported in in-vivo studies: intravenous,
intraperitoneal, or subcutaneuos.
Pharmacokinetics is characterised by-
• A plasma-time profile that is poly phasic with rapid
distribution half life(1hr) and long elimination half-life
reflecting slow elimination from the tissue.
• High binding to plasma proteins (>90% across species).
• Plasma clearance that is dominated by distribution into
tissues.
• Minor urinary or fecal excretion of the intact drug.
Distribution:
Highest conc. of oligonucleotides were found in kidney,
liver, spleen and lymph nodes, but can be measured in
almost every tissue except brain at 24hr after IV
adminstration.
Elimination:
While distribution of tissues relies on mechanism of
plasma clearance, whole body clearance is result of
metabolism and excreation of low molecular weight
oligonucleotides.
Tissue metabolism is slow and continuous process and
represent primary route of whole body elimination as
oligonucleotide fragments are excreted from body in
Pharmacodynamics
The mechanism of action of antisense compound is to
inhibit the gene expession sequence specifically by the
hybridization to mRNA through Watson-Crick base pair
interactions.
This is followed by the degradation of the target nRNA
through RNase H-dependent terminating mechanism.
Examples:
FOMVIRSEN
It represents original type of therapeutic oligonucleutide
which is a antisense compound.
Interferes with mRNA sequence in human.
Inhibits production of some viral proteins essential for viral
replication
Used in local treatment of cytomegalovirus retinitis.
Available in market as Vitravene.
PEGAPTANIB
It is an antagonist to endothelial growth factor.
It binds with high affinity to target molecule and
inactivates them.
Use in treatment of neovascular disease which is age
related macular degeneration.
Available in market as Macugen.
GENASENSE
Currently under phase III clinical trial.
Inhibits production of BCL-2 protein.
 Produced by cancer cell.
Applications
Antisence oligonucleotides are used to reduce levels of
protein synthesis by inhibiting mRNA processing or
translation.
It is used in treatment of cancer, cytomegalovirus retinitis
and familial hyperholesterolemia.
Common applications are aptamer design, Allel-specific
testing and triplex-forming oligonucleotides for dsDNA
binding.
Aptamers are used as sensors of cellular processes and
therapeutic tools. Aptamers that bind to cell surface
proteins can be use as drug delivery.
GENE THERAPY
It is an experimental technique
that uses genes to treat or
prevent diseases.
It is use to replace, manipulate
non-functional or malfunctional
gene with healthy gene.
Vector is used as carrier.
Virus is commonly used vector
which is genetically altered to
carry normal human DNA.
Retrovirus:
• Create dsDNA copies of their RNA genomes. This copies
of dsDNA is integrated into chromosome of host cell.
• Ex. HIV virus
Adenovirus:
• Virus with dsDNA genome causes respitaory, intestinal
and eye infections.
• Ex. Virus causing commom cold.
Herpes simplex virus:
• dsDNA infect a particular cell type, neurons. HSV-I is
common human pathogen causing cold sores.
Working of gene therapy
Gene to be inserted is genetically modified/ engineered
using vector called as virus (Adenovirus, retrovirus or
herpes simplex virus).
Virus is injected intravenously into specific tissue and
taken up by individual cells. This is in-vivo method.
The sample of a patient's tissue or cell is removed and
exposed to a vector in laboratory. Cells containing vector
is returned to patient's body. This method is called in-vitro
technique.
Application
Gene therapy is used to treat diseases with severe
combined immune deficiency, familial
hypercholesterolemia, cystic fibrosis, gausher's diseases.
Some protocols are aimed towards treating of-
• Cancer.
• Alzeimer's disease.
• Parkinson's diseases.
• Arthritis.
• Heart diseases.
References-
1. Shargel Leon, Yu.B.C Andrew, Shargel & Yu's,”Applied
Biopharmaceutics and Pharmacokinetics”, Seventh
Edition, Mc Graw Hill Education, Pg no. 618-625.
2. Breen Philip J., Jambhekar Sunil S.,”Basic
Pharmacokinetics”, Second Edition, Pharmaceutical
Press.
3. http://ghr.nlm.nih.gov/
Thank you!!

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Pharmacokinetics and pharmacodynamics of Biotechnological drugs-

  • 1. Pharmacokinetics and Pharmacodynamics of Biotechnology Drugs along with its applications (Proteins and Peptides, Monoclonal antibodies, Oligonucleotides, Gene therapy, Vaccines) Presented by, Snehal R. Tidke M.Pharm 2nd Semister, Pharmaceutics Department
  • 2. Biotechnology drugs The steady advances in cellular biology and biotechnology have allowed scientist to create new therapeutic entities mimicing the endogenous bioactive substances. These new products include Proteins and Peptides(PPTs), Monoclonal antibodies(mAbs), Oligonucleotides, Gene therapy treatment and Vaccines against microbiological and non microbiological diseases.
  • 4. Proteins and Peptides Naturally occuring large molecules with secondary or tertiary structure. Ensures proper functioning of body's biological events. Potent, less toxic, binds to their target. Biotechnologically proteins and peptides are developed rapidly. Majority of this drugs are administered parenterally either by subcutaneous, intramuscular or by systemic intravenous injection or infusion.
  • 6. Absorption Inhalation administration Offers ease of administration, provides large surface area of absortion, bypass first pass metabolism. Inhaled protein: DNase (pulmozyme) Enzyme used to break down mucus secretion in respiratory tracts of patients with cystic fibrosis. Exubera- systemic form of human insulin to exert therapeutic effect in inhaled form. on administration to lungs in dry powder inhaler, disposition and efficacy were found to be comparable to those of s.c adm of insulin and absorption was faster.
  • 7. Transdermal administration Offers advantageous route of bypassing metabolic degradation and chemical degradation in gastro intestinal tract and first pass metabolism in liver. Methods used to Facilitate Transdermal drug delivery system include sonophorosis and iontophorosis as it increses skin permeability to ionic compounds. Ex. Insulin, Interferon-ɣ and Epoetin-α
  • 8. Distribution Biodistribution studies od PPTs are performed to asses targeting to specific tissues and to identify major elimination organs. The volume if distribution is determined by physio- chemical properties, protein binding and dependency of active transport processes. After i.v application, PPTs usually follow biexpotential plasma concentration-time profile which is described by two-compartment p'kinetic model. Active tissue uptake can increase Vd of PPTs. Binding to endogeneuos protein structure can influence the distribution of PPTs.
  • 9. Elimination  Proteolysis: Proteases and peptidases enzymes are located within the cells, intracellular uptake is seen more in elimination rather than distribution process. Gastrointestinal: Major site of metabolism for orally administered PPTs. Presystemic metabolism is primarly seen. Parenterally administered PPTs metabolised in intestinal mucosa following intestinal secretion. Hepatic: Proteolysis usually starts with endopeptidases that attack in middle part of protein and resulting oligipeptides are then further degraded by exopeptidases.
  • 10. Renal Mediated through three process of mechanism: 1. Involves glomerular filtration of larger complex proteins and peptides followed by reabsorption into endocytic vesicles in proximal tubule and hydrolysis into small fragment . 2. Glomerular filtration is followed by luminal brush border membrane of proximal tubules. 3. Peritubular extraction of peptides and proteins from post glomerulatr capillaries and intracellular metabolism.
  • 11. Examples- Desmopressin: Small peptide- 1.18 KDa Has sufficient bioavailability after intranasal adm to elicit a systemic therapeutic response. Used as antidiuretic hormone Oxytocin: Peptide with 9 amino acid residues with molecular mass 1.007 KDa. Given bi i.v infusion Facilitates childbirth.
  • 12. Antihaemophilic factor: Large glycoprotein- 320 KDa produce by recombinant DNA technology. Elimination half life-14.6 hrs. Administration- by intravenous infusion. Used in treatment of haemophilia.
  • 13. As short elimination halt life is recorded in i.v studies, several PPTs are given by s.c or i.m route rather than i.v as delayed absorption causes plasma drug conc. to remain high for appreciable period of time as shown below- DRUG Intravenous route (in hrs) Subcutaneous route (time in hrs) Intamuscular route (time in hrs) Treatment Insulin 0.08-0.12 1.5 - Diabetes Parathyroid hormone(forteo) 0.083 1.0 - Osteoporosis Sargramostim 1.0 2.77 - Mylois stimulation Engraftment(bone marrow transplant) Human growth harmone 0.33-0.5 3.8 4.9 Growth harmone defciency Interferon α 5.1 - 7 Chronic hepatitis C
  • 14. The site and mechanism of elimination may be determined by- charge,oil/water partition coeficient, presence of sugar or functional group or mol. weight. ADME differs depending on the size of PPTs as shown in table: Size of PPTs Molecular weight (in KDa) DESCRIPTION Small proteins <60  Absorption: Proximal tubules (endocytosis)  lysosomal degradation if complex proteins are present  metabolised by enzymes in case of v.small linear peptide ex. bradykinin Small polypeptide <1 Transportation to hepatocytes for degradation occurs by • passive diffusion (if lipophilic) • carrier mediated uptake (if polor) Moderate size protein 50-200 Receptor mediated endocytosis in liver Large protein 200-400 In association with immunoglobulins by phagocytosis
  • 16. Monoclonal antibodies (Ig molecule) Produced by recombinamt DNA technology Results in molecules being identical in structure and with high purity. Most of the clinically developed or approved mAbs are administered by intravenous infusion. Produced sufficiently in large quantities for use as therapeutic agent. MAbs are humanised to prevent incidence of hypersensitivity reaction that can occur from antibodies from foriegn species. Bexxar and Zevalin are new class of radioimmunotherapy drugs use to kill cancer cells.
  • 17. P'kinetic of mAbs Absorption: Extra vascular routes have been chosen as alternatives, including subcutaneous and intramuscular adminstration. The mAbs enter lymphatic system by convective flow of interstitial fluid into porous lymphatic vessel and are further transported unidirectionally into venous system.  It has been shown that antibodeis can reach systemic circulation after oral administration, but to very small extent. The antibodies pass the intestinal epithelium not by passive transcellular but by receptor mediated transcellular or paracellular transport.
  • 18. Distribution Distribution is poor due to high molecular mass and hydrophilicity/polarity of the molecules. Transport: Permeation across cells/tissues is accomplished by transcellular or paracellular transport, involving process of diffusuion, convection and cellular uptake. Due to physio- chemical properties, extent of diffusion across cell membrane in transcellular transport is minimal. Endocytosis is absorptive process of large and polar molecules involving formation of intracellular vesicles from parts of cell membranes.
  • 19. Elimination Clearance: As mAbs do not go glomerulatr filtration due to large size, tubular sectretion has not been reported to occur to any significant extebnt for mAbs. Thus renal elimination is uncommon or low for mAb with exception for low molecular mass mAbs. Biliary elimination is has been reported for IgA molecules and only to very small extent.Therefore, total clearance (CL) does not comprise renal or biliary clearance.
  • 20. Some of the approved mAb drugs- DRUG YEAR OF APPROVAL ELIMINATION HALF LIFE (in hrs) TARGET APPLICATION Muromonab 1986 18 CD3 receptor Prevents rejection of kidney transplant Abciximab 1994 0.16-0.5 (>10 min) Inhibits plateplat aggregation by targeting glycoprotein Prevention of thrombosis in percutaneuos coronary intervention Bevacizumab 2004 20 days Vascular endothelial groth factor Colorectal cancer, Lung cancer, Metastatic lung cancer
  • 21. Applications 1. Cancer treatment- mAbs against leukemia and lymphomas have been used in treatment with variable results. 2. Imaging diagnosis- mAbs is used with radioactive markers to locate and visualise location and extent of the tumors. 3. Target specific delivery- mAbs used along with liposomes. Ex. prokinase congugate with mAbs to disslove fibrin clots. 4. Transplant rejection suppression- In kidney transplant, mAbs against CD3 is used.CD3 causes rejection
  • 22. OLIGONUCLEOTIDES Therapeutic Oliginucleotides are short strands of nucleotides that interfere with pathogenic proteins. Oligonucleotides showing activity can serve as basis for product of MAb or other component that may be eaily approved for clinical use. Only two oligoneucleotides have been approved for clinical use- 1. Fomvirsen - FDA approval in 1998 2. Pegaptanib - FDA approval in 2004
  • 23. PHARMACOKINETICS: Absorption- Antisense oligonucleotides are majorly administered parenterally as reported in in-vivo studies: intravenous, intraperitoneal, or subcutaneuos. Pharmacokinetics is characterised by- • A plasma-time profile that is poly phasic with rapid distribution half life(1hr) and long elimination half-life reflecting slow elimination from the tissue. • High binding to plasma proteins (>90% across species). • Plasma clearance that is dominated by distribution into tissues. • Minor urinary or fecal excretion of the intact drug.
  • 24. Distribution: Highest conc. of oligonucleotides were found in kidney, liver, spleen and lymph nodes, but can be measured in almost every tissue except brain at 24hr after IV adminstration. Elimination: While distribution of tissues relies on mechanism of plasma clearance, whole body clearance is result of metabolism and excreation of low molecular weight oligonucleotides. Tissue metabolism is slow and continuous process and represent primary route of whole body elimination as oligonucleotide fragments are excreted from body in
  • 25. Pharmacodynamics The mechanism of action of antisense compound is to inhibit the gene expession sequence specifically by the hybridization to mRNA through Watson-Crick base pair interactions. This is followed by the degradation of the target nRNA through RNase H-dependent terminating mechanism.
  • 26. Examples: FOMVIRSEN It represents original type of therapeutic oligonucleutide which is a antisense compound. Interferes with mRNA sequence in human. Inhibits production of some viral proteins essential for viral replication Used in local treatment of cytomegalovirus retinitis. Available in market as Vitravene.
  • 27. PEGAPTANIB It is an antagonist to endothelial growth factor. It binds with high affinity to target molecule and inactivates them. Use in treatment of neovascular disease which is age related macular degeneration. Available in market as Macugen. GENASENSE Currently under phase III clinical trial. Inhibits production of BCL-2 protein.  Produced by cancer cell.
  • 28. Applications Antisence oligonucleotides are used to reduce levels of protein synthesis by inhibiting mRNA processing or translation. It is used in treatment of cancer, cytomegalovirus retinitis and familial hyperholesterolemia. Common applications are aptamer design, Allel-specific testing and triplex-forming oligonucleotides for dsDNA binding. Aptamers are used as sensors of cellular processes and therapeutic tools. Aptamers that bind to cell surface proteins can be use as drug delivery.
  • 29. GENE THERAPY It is an experimental technique that uses genes to treat or prevent diseases. It is use to replace, manipulate non-functional or malfunctional gene with healthy gene. Vector is used as carrier. Virus is commonly used vector which is genetically altered to carry normal human DNA.
  • 30. Retrovirus: • Create dsDNA copies of their RNA genomes. This copies of dsDNA is integrated into chromosome of host cell. • Ex. HIV virus Adenovirus: • Virus with dsDNA genome causes respitaory, intestinal and eye infections. • Ex. Virus causing commom cold. Herpes simplex virus: • dsDNA infect a particular cell type, neurons. HSV-I is common human pathogen causing cold sores.
  • 31. Working of gene therapy Gene to be inserted is genetically modified/ engineered using vector called as virus (Adenovirus, retrovirus or herpes simplex virus). Virus is injected intravenously into specific tissue and taken up by individual cells. This is in-vivo method. The sample of a patient's tissue or cell is removed and exposed to a vector in laboratory. Cells containing vector is returned to patient's body. This method is called in-vitro technique.
  • 32. Application Gene therapy is used to treat diseases with severe combined immune deficiency, familial hypercholesterolemia, cystic fibrosis, gausher's diseases. Some protocols are aimed towards treating of- • Cancer. • Alzeimer's disease. • Parkinson's diseases. • Arthritis. • Heart diseases.
  • 33. References- 1. Shargel Leon, Yu.B.C Andrew, Shargel & Yu's,”Applied Biopharmaceutics and Pharmacokinetics”, Seventh Edition, Mc Graw Hill Education, Pg no. 618-625. 2. Breen Philip J., Jambhekar Sunil S.,”Basic Pharmacokinetics”, Second Edition, Pharmaceutical Press. 3. http://ghr.nlm.nih.gov/