Professional Documents
Culture Documents
9 BPK
9 BPK
PHARMACOKINETICS
PRESENTED BY
ARAVINDH.G
M.PHARM (SEM-II).
DEPT. OF PHARMACEUTICS.
MADRAS MEDICAL COLLEGE
1
CHENNAI-03.
CONTENTS
Modified release drug products.
Targeted drug delivery systems.
Biotechnological products.
Introduction of PK & PD.
Drug interaction.
PK & PD of biotechnology drugs.
Proteins and peptides.
Monoclonal antibodies.
Oligonuclotides
Vaccines and gene therapies.
References
2
GENERAL APPLICATION
3
MODIFIED RELEASE DRUG PRODUCT
5
The term modified-release drug product is used to describe
products that alter the timing and/or the rate of release of
the drug substance.
Several types of modified-release oral drug products are
recognized:
Extended-release drug products. A dosage form that allows at
least a twofold reduction in dosage frequency as compared to
that drug presented as an immediate-release (conventional)
dosage form.
Examples of extended-release dosage forms include controlled-
release, sustained-release, and long-acting drug products.
6
Delayed-release drug products. A dosage form that releases a
discrete portion or portions of drug at a time other than
promptly after administration. (eg, enteric-coated aspirin and
other NSAID products).
Targeted-release drug products. A dosage form that releases
drug at or near the intended physiologic site of action.
Targeted-release dosage forms may have either immediate- or
extended-release characteristics.
Orally disintegrating tablets (ODT). ODT have been
developed to disintegrate rapidly in the saliva after oral
administration. ODT may be used without the addition of
water.
The drug is dispersed in saliva and swallowed with little or no
water. 7
TARGETED DRUG DELIVERY
SYSTEMS
Acceleration of delivery of drugs to organs and tissues.
Enhanced delivery by cationization
Alteration of net charge by chemical modification is also an
effective approach for targeted delivery of protein drugs
Cationic macromolecules are rapidly taken up by the liver,
primarily hepatocytes, via electrostatic interaction with
negatively charged cell surfaces.
Although slower than that observed in receptor-mediated
endocytosis.
Massive internalization of the proteins into the cell interior
occurs by absorptive endocytosis.
8
Receptor-mediated delivery of therapeutic proteins
9
Receptor-mediated delivery of particulate carriers
10
INTRODUCTION TO PK & PD
11
Absorption
The main factor which relates to absorption of drugs is the route of
administration.
Physiological considerations in absorption are blood flow, total
surface area, time of arrival of the drug and time of drug at
absorption site.
Other considerations for absorption are solubility, chemical stability
and how soluble the drug is in lipids.
Distribution
Drugs are distributed into major body fluids (e.g. Plasma).
Specific tissues may take up certain drugs (e.g. Iodine is taken up by
the thyroid gland).
Drug distribution is affected by the extent that the drug binds to
plasma proteins.
Drug distribution is affected by barriers (e.g. the placenta and the 12
BBB).
Biotransformation
This is a process of metabolizing drugs in the body.
It occurs mainly in the liver and is therefore often called hepatic
metabolism.
Some drugs are given that are activated by this hepatic
metabolism, these are called pro-drugs.
Drug metabolism is split into two phases in the liver.
An example of phase I metabolism would be oxidation,
An example of phase II metabolism would be conjugation.
Excretion
Excretion includes renal elimination and faecal elimination.
The main method of renal elimination is by active glomerular
filtration.
13
Drugs can also be eliminated by passive methods in the distal
tubules.
Drugs can be eliminated from the body in bile and so removed in
the faeces.
General and molecular aspects
15
Agonistic and antagonistic drug action
Agonists activate receptors to produce a response. Antagonists
bind with receptors but do not activate them or cause a
response.
They can actually block the activation of receptors. Partial
agonists produce a response.
However, this is less than would be expected by a full agonistic
drug.
Inverse agonists are drugs which can reduce the normal
activity of the cell.
Competitive antagonists are drugs that prevent activation of the
cell by their normal agent.
Non-competitive antagonists are drugs that may block the
receptor but not in a permanent way. 16
PHARMACOKINETIC DRUG INTERACTIONS:
1. ALTERATIONS IN ABSORPTION
a. Complexation/Chelation
b. Altered GI transit
c. Altered Gastric PH
d. Alteration in gastrointestinal microflora
2. ALTERATIONS IN PLASMA PROTEIN BINDING
3. ALTERATIONS IN HEPATIC METABOLISM
a. Induction of metabolism
b. Inhibition of metabolism
4. ALTERATIONS IN RENAL CLEARANCE(EXCRETION)
a. Increased renal blood flow
b. Inhibition of active tubular secretion
17
c. Alterations in tubular re absorption
ALTERATIONS IN ABSORPTION :
A. Complexation/ Chelation :
Antacids (Mg2+, Al3+ ions) make complex with Tetracycline,
Ciprofloxacin reduced absorption of Tetracycline.
B. Altered GI Transit:
Anticholinergics Block M3 receptors reduce motility delays the
absorption of Acetaminophen
C. Altered gastric pH:
H2 blockers (Ranitidine, Cimetidine) reduce acid secretion
increase. pH reduce dissolution of Ketoconazole reduce
absorption of ketoconazole.
D. Altered Gastrointestinal microflora:
Antibiotics kills the microflora of GIT Reduce the absorption of
oral contraceptives unwanted pregnancy. 18
ALTERATIONS IN PLASMA PROTEIN BINDING :
Alterations in Plasma protein binding Sulfonamides,
Phenytoin (Highly protein bound) Displaces the Warfarin from
plasma protein binding elevates free Warfarin level increase
anticoagulant effect increase the risk of Bleeding
ALTERATIONS IN HEPATIC METABOLISM :
A.Induction of hepatic metabolism:
Phenobarbital (CYP Enzyme inducer) Increase the
metabolism of Warfarin Reduce the plasma level of warfarin
decreased anticoagulant effect.
B. Inhibition of Hepatic metabolism:
Metronidazole (CYP enzyme inhibitor) inhibits metabolism
of warfarin elevation of plasma Warfarin levels raise the
anticoagulant effect increased risk of Bleeding
19
ALTERATIONS IN RENAL CLEARANCE:
22
In the future, biopharmaceuticals may be used against the
AIDS virus, different types of cancer, asthma, Parkinson’s
and Alzheimer’s disease.
There are different groups of biopharmaceuticals, including:
antibiotics, blood factors, hormones, growth factors,
cytokines, enzymes, vaccines and monoclonal antibodies.
23
PROTEIN
Proteins are classified into two major groups based on their
shape.
Fibrous proteins are long, rod-shaped molecules that are
insoluble in water and physically tough. Fibrous proteins,
such as the keratins found in skin, hair, and nails, have
structural and protective functions.
Globular proteins are compact spherical molecules that
are usually water- soluble and have dynamic functions.
Nearly all enzymes have globular structures. Examples
immunoglobulins and the transport proteins hemoglobin
and albumin (a carrier of fatty acids in blood).
24
On the basis of composition, proteins are classified as simple
or conjugated.
Simple proteins, such as serum albumin and keratin, contain
only amino acids.
conjugated protein, consists of a simple protein combined
with a nonprotein component.
The nonprotein component is called a prosthetic group.
A protein without its prosthetic group is called an apoprotein.
A protein molecule combined with its prosthetic group is
referred to as a holoprotein.
Prosthetic groups typically play an important, even crucial,
role in the function of proteins.
25
Conjugated proteins are classified according to the
nature of their prosthetic groups.
For example,
Glycoproteins contains a carbohydrate component.
Lipoproteins contains lipid molecules.
Metalloproteins contain metal ions.
Phosphoproteins contain phosphate groups.
Hemoproteins possess heme groups
26
PROTEIN STRUCTURE
Primary structure
Secondary structure
Tertiary structure
Quaternary structure
28
DISTRIBUTION
The volume of distribution of a peptide or protein drug is
determined largely by its physico-chemical properties (e. g.,
charge, lipophilicity), protein binding, and dependency on
active transport processes.
Due to their large size – and therefore limited mobility through
biomembranes – most therapeutic proteins have small volumes
of distribution, typically limited to the volumes of the
extracellular space.
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.
29
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
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.
30
31
MONOCLONAL ANTIBODIES
32
ABSORBTION
Route-i.v, i.m, s.c
The mechanism of absorption after SC or IM administration is
thought to occur via the lymphatic system.
From the lymphatic vessels, the mAbs are transported uni-
directionally into the venous system.
Distribution
In general, the distribution of classical mAbs in the body is
poor. Limiting factors are, in particular, the high molecular
mass and the hydrophilicity/polarity of the molecules.
Nevertheless, mAbs are able to reach targets outside the
systemic circulation.
33
Transport
Permeation of mAbs across the cells or tissues is
accomplished by transcellular or paracellular transport,
involving the processes of diffusion, convection, and cellular
uptake.
34
ELIMINATION
Clearance
As glomerular filtration has an approximate molecular size
limit of 20–30 kDa, mAbs do not undergo filtration in the
kidneys due to their relatively large size.
The situation is different, however, for low molecular-mass
antibody fragments, which can be filtered.
Tubular secretion has not been reported to occur to any
significant extent for mAbs, and peptides/small proteins are
readily reabsorbed in the proximal or distal tubule of the
nephron (potentially also mediated by the neonatal Fc
receptor, Fc-Rn), or are even metabolized.
Thus, renal elimination in total is uncommon or low for
mAbs. Biliary excretion of mAbs has been reported only for
IgA molecules, and only to a very small extent. 35
Therefore, total clearance (CL) does usually not comprise
renal or biliary clearance.
Across mAbs, clearance estimates range from about 11 to
almost 400 mL/h.
36
37
OLIGONUCLEOTIDES
39
Examples of procedures that use oligonucleotides
include DNA microarrays, Southern blots, ASO
analysis, fluorescent in situ hybridization (FISH), PCR, and
the synthesis of artificial genes.
Oligonucleotides are also indispensable elements in antisense
therapy.
Oligonucleotides composed of 2'-deoxyribonucleotides
(oligodeoxyribonucleotides) are fragments of DNA and are
often used in the polymerase chain reaction, a procedure that
can greatly amplify almost any small amount of DNA.
There, the oligonucleotide is referred to as a primer,
allowing DNA polymerase to extend the oligonucleotide and
replicate the complementary strand.
40
Oligonucleotides are chemically synthesized using building
blocks, protected phosphoramidites of natural or chemically
modified nucleosides or, to a lesser extent, of non-nucleosidic
compounds.
The oligonucleotide chain assembly proceeds in the direction
from 3'- to 5'-terminus by following a routine procedure
referred to as a "synthetic cycle".
Completion of a single synthetic cycle results in the addition of
one nucleotide residue to the growing chain.
41
Vaccines
Vaccines Currently, vaccines are not only developed against
infectious diseases, but also against drug abuse (nicotine,
cocaine) and against allergies, cancer and Alzheimer’s
disease.
Despite the success of conventional vaccines, there are still
many infectious diseases and other chronic diseases against
which no effective vaccine exists.
In addition, the growing resistance to the existing arsenal of
antibiotics increases the need to develop vaccines against
common bacterial infections.
42
Although conventionally produced vaccines are generally
harmless, some of them may, rarely, contain infectious
contaminants.
Vaccines whose active ingredients are recombinant antigens do
not carry this slight risk.
Vaccines produced by recombinant DNA techniques have been
used to combat seasonal influenza virus and hepatitis A and B.
The first vaccine against hepatitis B was made from plasma
derived from patients with chronic hepatitis B, and a
recombinant vaccine whose sole active ingredient is a
recombinant antigen has now replaced it.
43
Immunotherapy is a type of biological therapy. It aims to
enhance the body’s immune response, Biological therapies use
substances made from living organisms to treat disease.
Immunotherapy is a treatment that strengthens the natural
ability of the patient’s immune system to fight foreign bodies.
Instead of targeting the person’s foreign cells directly,
immunotherapy trains a person’s natural immune system to
recognize foreign cells and selectively target and kill them.
44
Immunotherapy's do this in one of two ways:
By enabling the immune system to mount or maintain a
response
By suppressing factors that prevent the immune response
45
GENE THERAPY
Gene therapy is a novel treatment method which utilizes
genes or short oligonucleotide sequences as therapeutic
molecules, instead of conventional drug compounds.
Gene therapy involves the introduction of one or more
foreign genes into an organism to treat hereditary or acquired
genetic defects.
In gene therapy, DNA encoding a therapeutic protein is
packaged within a "vector", which transports the DNA inside
cells within the body.
The disease is treated with minimal toxicity, by the expression
of the inserted DNA by the cell machinery
46
There are several approaches for correcting faulty genes; the
most common being the insertion of a normal gene into a
specific location within the genome to replace a non
functional gene.
1. Somatic gene therapy
2. Germ line gene therapy
48
GENE AUGMENTATION THERAPY (GAT)
49
TARGETED KILLING OF SPECIFIC CELLS
50
Targeted Inhibition of Gene Expression
This is to block the expression of any diseased gene or a new
gene expressing a protein which is harmful for a cell. This is
particularly suitable for treating infectious diseases and some
cancers.
51
GENE THERAPY APPROACHES
52
METHODS OF GENE THERAPY
54
REFERENCES
1. Brahmankar.D.M, Jaiswal.B.sunil, Biopharmaceutics and
pharmacokinetics–Atreatise, vallabh prakashan, Delhi,2005.
2. Pharmacokinetics and Pharmacodynamics of Biotech Drugs
Edited by Bernd Meibohm, 2006 WILEY-VCH Verlag
GmbH & Co. KGaA, Weinheim, Germany.
3. Leon Shargel, Andrew B.C. yu, Applied Biopharmaceutics
& Pharmacokinetics, Seventh Edition.
4. http;//Google.co.in/NPTEL – Bio Technology – Genetic
Engineering & Applications, Joint initiative of IITs and IISc
– Funded by MHRD.
5. http;//Google.co.in/Mc Graw Hills/access pharmacy/Applied
Pharmacokinetics and Pharmacodynamics.
55
THANK YOU…
56