pharmacokinetics and dynamics of biotechnoloical pdts

1. PHARMACOKINETICS&
PHARMACODYNAMICS
OF BIOTECHNOLOGICAL
DRUGS
Submitted By
Sujitha Mary
M Pharm
St Joseph College Of Pharmacy

2. INTROUCTION
 Biotechnological drugs are the subset of the therapeutic group of biologics.
 Therapeutic biologic products, or biologics, are defined by the U.S. Food and
Drug Administration (FDA) as any virus, therapeutic serum, toxin, antitoxin,
or analogous product applicable to the prevention, treatment or cure of
diseases or injuries of man. •Examples:- proteins, monoclonal
antibodies……..
 Pharmacokinetics characterize what the body does to the drug.
 Pharmacodynamics assesses what the drug does to the body.

3. PHARMACOKINETICS OF PEPTIDE AND
PROTEINS
❑Administration pathways:
 Oral administration
•Therapeutically inactive upon oral administration due to
➢High gastrointestinal enzyme activity
➢ low permeability through gastrointestinal mucosa
 Administration by injection/infusion
•Achieve the highest concentration in biological system
•There is a reduced bioavailability incase of subcutaneous and intramuscular
route compared to intravenous route

4.  The true absorption rate constant Ka in this case Ka=Fkapp F-bioavailability
compared to IV infusion Kapp-apparent absorption rate constant

5. ❖Inhalational administration
•Inhalational delivery of protein peptide offer the advantage of
➢Ease of administration
➢Presence of large surface area available for absorption
➢High vascularity of administration site
➢Bypass of hepatic first pass metabolism
•Disadvantages
➢Presence of certain proteases in lungs
➢Potential local side effect of the inhaled agents on the lung tissue
➢Molecular weight limitation Example:-Inhaled recombinant human insulin
product with
Exubera
Dornase-α-for the treatment of cystic fibrosis

6. ❖Intranasal administration
•intranasal administration of peptides and proteins offers the advantages of
➢ease of administration,
➢delivery to a surface area rich in its vascular and lymphatic network,
➢ bypassing of hepatic first-pass metabolism
•Examples:-calcitonin, oxytocin, LH-RH, growth hormone,intreferone
•Limitation
➢high variability in absorption associated with the site of deposition,
➢ the type of delivery system,
➢changes in mucus secretion and mucociliary clearance,
➢presence of allergy, hay fever, or the common cold in the target population

7. ❖Transdermal administration
•It 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
sonophoration and iontophoresis.
•Both methodologies increase skin permeability to ionic compounds
• sonophoration by applying low-frequency ultrasound,
•iontophoresis by applying a low-level electric current.

8. ❖Peroral administration
•Oral delivery of peptides and proteins would be the preferred route of
administration if bioavailability issues could be overcome, as it offers the
advantages of convenient, pain-free administration.
•Methods
➢Use of absorption enhancers
➢Microencapsulation
➢amino acid backbone modification,
➢alternate formulation design,
➢chemical conjugation to improve their resistance to degradation,
➢inhibition of enzymatic degradation by co-administration of protease
inhibitors

9. 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,
➢ 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 spac

10.  After IV application, peptides and proteins usually follow a biexponential
plasma concentration–time profile.
 It can be described by a two-compartment pharmacokinetic model.
 Central compartment -vascular space and the interstitial space of well-
perfused organs with permeable capillary walls, especially liver and kidneys.
 Peripheral compartment - interstitial space of poorly perfused tissues such
as skin and (inactive) muscle

11. ELIMINATION
 They are eliminated by metabolism via the same catabolic pathways as
endogenous or dietary proteins, resulting in amino acids.
 Non-metabolic elimination pathways such as renal or biliary excretion are
generally negligible for most peptides and proteins.
 The elimination of peptides and proteins can occur unspecifically almost
everywhere in the body, or it can be limited to a specific organ or tissue.
➢Proteolysis
•By the action of proteases and peptidases
•Not only limited to the liver, kidneys, and gastrointestinal tissue, but also
include the blood and vascular endothelium as well as other organs and
tissues.

12. ➢Gastrointestinal Elimination
•major site of metabolism
•primary reason for their lack of oral bioavailability
➢Renal elimination
•For parenterally administered and endogenous peptides and proteins
•major elimination organ if the peptide/protein size is less than the glomerular
filtration limit of ~60 kDa
➢Hepatic Elimination
•The rate of hepatic metabolism is dependent on specific amino acid sequences
in the protein.
•Substrates for hepatic metabolism include insulin, glucagon, and t-Pas
•An important first step in the hepatic metabolism of proteins and peptides is
uptake into the hepatocytes.

13. PHARMACOKINETICS OF MONOCLONAL
ANTIBODIES
 Monoclonal antibodies have a significant potential as therapeutic agents
because of their ability to bind to specific structures as targets.
 This principle of “targeted therapy” results in high clinical efficacy whilst
minimizing adverse reactions, and thus increases mAb tolerability and use.
 Example:- Natalizumab (Tysabri) can be used for the treatment of multiple
sclerosis
 Antibodies display several different effector functions and modes of action as
part of their function in the human immune system.

14. BIOLOGICAL EFFECTOR FUNCTIONS OF MABS
 Antibody-dependent cellular cytotoxicity by natural killer (NK) cells.
 Complement-dependent cytotoxicity (CDC).
 Neutralization of exotoxins and viruses.
 Prevention of bacterial adherence to host cells.
 Membrane attack complex (MAC) resulting in cytolysis.
 Agglutination of microorganisms.
 Immobilization of bacteria and protozoa.
 Opsonization.

15. MODES OF ACTION OF MABS
 Antibody-Dependent Cellular Cytotoxicity (ADCC)
 Complement-Dependent Cytotoxicity
 Blockage of Interaction between (Patho)Physiological Substance and
Antigen
 Conjugated Unlabeled mAbs

16. PHARMACOKINETIC CHARACTERISTICS OF
mABS
 ➢Absorption
 Due to their high molecular mass (and other reasons), the vast majority of
mAbs are administered by intravenous (IV) infusion.
 IV infusions represent the most inconvenient as well as time- and cost-
consuming means of administration.
 Hence extravascular routes have been chosen as alternatives, including
subcutaneous administration (SC; e. g., adalimumab, efalizumab) and
intramuscular administration (IM; e. g., palivizumab).
 The mechanism of absorption after SC or IM administration is thought to
occur via the lymphatic system.

17. ➢Distribution
 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
➢Transport
 Permeation of mAbs across the cells or tissues is accomplished by transcellular
or paracellular transport.
 It involve the processes of diffusion, convection, and cellular uptake.
 Due to their physico-chemical properties, the extent of passive diffusion of
classical mAbs across cell membranes in transcellular transport is minimal.
 Cellular uptake of mAbs takes place via endocytosis and can be either receptor
mediated,or non-receptor-mediated

18. ➢Volume of Distribution
 The estimated volumes of distribution are small and relatively homogeneous.
 small-sized antibody fragments can penetrate tissues more easily, might
potentially cross the blood–brain barrier, and can be delivered locally to the
lung through inhalation.
➢Elimination
 Clearance
✓mAbs do not undergo filtration in the kidneys due to their relatively large size.
✓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

19.  Major elimination routes are
➢Proteolysis
➢Binding to antigen
➢Binding to anti-idiotype antibodies

20. PHARMACOKINETICS AND PHARMACODYNAMICS
OF OLIGONUCLEOTIDES
 A polynucleotide whose molecules contain a relatively small number of
nucleotides.
 It include antisense oligonucleotides (ASO), RNA interference (RNAi), and
aptamer RNAs.
 ASO and RNAi oligonucleotides are intended mainly for modulating gene
and protein expression.
 Aptamer oligonucleotides can act as “chemical antibodies” to modulate
functions of proteins and other macromolecules.

21. PHARMACOKINETICS:
❖Absorption
 The primary route of administration for antisense oligonucleotides for systemic
applications is by parenteral injection, either intravenous (i.v.) infusion or
subcutaneous injection.
 The plasma half-life following SC administration is longer than that after IV
injection, and is indicative of continued absorption from the injection site during
the disposition phase.
 Topical or local application of oligonucleotides generally results in localized
distribution and activity.
 Oligonucleotides do not cross the blood–brain barrier (BBB) following systemic
administration .
 But it can be directly injected or infused into the cerebrospinal fluid with resultant
broad distribution to spinal cord and brain

22. ❖Distribution
 The highest tissue accumulation has been observed in kidney, liver, spleen,
lymph nodes, adipocytes and bone marrow
 oligonucleotides that lack charge are less extensively or more weakly bound
to plasma proteins exhibit more rapid clearance from blood primarily due to
either metabolism in blood or excretion in urine.
 At clinically relevant concentrations in plasma, saturation of binding does not
occur.
 Topical or local application of oligonucleotides generally results in localized
distribution and activity

23. ❖Metabolism:
 Oligonucleotides are metabolized by nucleases
 It do not serve as substrates for P450 oxidative metabolism.
 Parent drug and its nuclease generated smaller oligonucleotide fragments
are excreted in urine.
❖Excretion
 Oligonucleotides and their shortened oligonucleotide metabolites are
excreted primarily in urine.

24. PHARMACODYNAMICS:
 They inhibit gene expressions sequence-specifically by hybridization to
mRNA through Watson–Crick base pair interactions.
 Degradation of the target mRNA through an RNase Hdependent terminating
mechanism.
 Finally it prevents translation of the encoded protein product, or the disease-
causing factor in a highly sequence-specific manner.
 Example:-Fomivirsenfor the treatment of cytomegalovirus retinitis in patients
withAIDS Mipomersen for the treatment of homozygous familial
hypercholesterolaemia (HoFH), a rare genetic disorder that leads to
excessive levels of low-density lipoprotein (LDL) cholesterol.

25. GENE THERAPY
 Definiton: an experimental technique for correcting defective genes that are
responsible for disease development.
 The most common form of gene therapy involves inserting a normal gene to
replace an abnormal gene
 Gene therapy utilizes the delivery of DNA into cells, which can be
accomplished by a number of methods.
 The two major classes of methods : recombinant viruses – VIRAL VECTOR
naked DNA or DNA complexes –
❑NONVIRAL VECTOR

26. ❖Naked DNA
 It is generally difficult to determine pharmacokinetic parameters for naked
DNA as it is rapidly and extensively degraded in plasma.
 The clearance from plasma after IV administration is even more rapid.
 After intramuscular and intradermal injections of naked plasmid showed that
DNApersisted at the injection site and in lymph nodes up to 28 days after
injection.
❖Non-Viral Vectors
 Chemical vectors include polycationic carriers such as liposomes
(lipoplexes) and polymers (polyplexes).
 These carriers avoid the DNAsize limitations and immunogenicity associated
with viral vectors

27.  After administration, non-viral vectors encounter resistance due to the barriers in
gene delivery
❑Systemic barriers
 degradation of DNAby plasma nucleases,
 Opsonization of DNA complexes by negatively charged serum components,
 Uptake by the reticuloendothelial system
 Distribution of DNA to non-target tissues
❑Cellular barriers
 Internalization at the cell surface
 Endosomal release
 Cytoplasmic degradation
 Translocation into the nucleus

28.  In lipoplex DNA is usually encapsulated inside the liposome. Although this is
beneficial in that it protects the DNAfrom degradation. 3 types of lipids:
anionic (negatively charged)
neutral
cationic (positively charged).
 Polyplex are the Complexes of polymers with DNA.
 Consist of cationic polymers and their production is regulated by ionic
interactions.

29. ❖Viral Vectors
 Recombinant adeno-associated virus (rAAV) has been widely used as a
therapeutic gene delivery vector.
 It binds to both heparin sulfate proteoglycans and fibroblast growth factor
receptors as an essential step for cellular entry.
 This accounts for their different biodistribution properties when injected into brain
and other tissues
 The pharmacokinetic properties of a vector depend on
✓route and duration of administration,
✓the dose,
✓The physical properties of the vector (e. g., size),
✓ cell-tropism.

30.  IV administration of rAAV generally results in the vector accumulating
primarily in the liver, although smaller amounts spread to many tissues
including the spleen, smooth muscle, striated muscle and kidneys.
 The route of vector administration affected its spread and distribution.
 Elimination of viral vectors within tissues or within the blood compartment
results from the action of both endonucleases and exonucleases.
 Intramuscular injection resulted in high and localized transgene production
especially in the liver, while IV injection produced low expression in this
tissue.

31. CONCLUSION
 Advances in biotechnology have triggered the development of numerous
new drug products.
 Biotechnological drugs include not only therapeutically used peptides and
proteins, including monoclonal antibodies, but also oligonucleotides and
DNApreparations for gene therapy.
 The dose–concentration–effect relationship is defined by the
pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of a drug.
 PK/PD concepts in all stages of preclinical and clinical drug development is
one potential tool to enhance the information gain during drug development.
 PK/PD analysis supports the identification and evaluation of drug response
determinants.

32. REFERENCE:•
 Meibohm,B.,andH.Derendorf.2002.Pharmacokinetic/pharmacodyn amic
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 Brambell, F.W.R.,W.A. Hemmings, and I.G. Morris. 1964. A theoretical model
of -globulin catabolism. Nature 203 : 1352– 1355.
 Baker, B.F., and B.P. Monia. 1999. Novel mechanisms for antisense-
mediated regulation of gene expression. Biochim. Biophys. Acta 1489 : 3–
18.
 Anderson,W.F. 1998. Human gene therapy.Nature 392 : 25–30