Title: Pharmacokinetics in Design of Novel Drug Delivery Systems By Prof' R' N' Saha BITS, Pilani, India
1Pharmacokinetics in Design of Novel Drug Delivery
SystemsBy Prof. R. N. SahaBITS, Pilani,
India
2- Drug therapy is a dynamic process. When a drug
product is administered, absorption continues for
a finite period of time and distribution,
metabolism, and excretion of drug continues at
various rates. - Normally, the aim of a drug therapy is to achieve
and maintain effective concentration of drug at
the receptor site. However, as the body
constantly tries to eliminate the drug, it is
necessary to balance absorption against
elimination to maintain the desired
concentration. Often the receptor site are tucked
away in a specific organ or tissue of the
body, i.g., CNS, and it is necessary to depend on
the blood supply to distribute the drug from the
site of administration, such as GIT, to the site
of action. - To achieve the goal by overcoming those processes
and barrier, development of proper drug delivery
system is most important.
3- The development of drug delivery system is
extremely complex and interwoven, and it requires
a team approach. Pharmacokinetic and
biopharmaceutical aspects are very important in
this endeavor. - Basic pharmacokinetic understanding of a given
drugs disposition in human body is essential for
proper design of delivery systems. - Pharmacokinetic principles are being applied by
clinicians to the rational design of dosage
regimens. - It has become more relevance due to stringent
regulatory requirements. - Pharmaceutical dosage form design, thus, must be
based on a sound knowledge of the pharmacology,
physico-chemical properties, pharmacokinetics,
pharmacodynamics of the drug and regulatory
requirements.
4Pharmacokinetics
- Study and characterization of the time course of
drug absorption, distribution, metabolism and
excretion, and the relationship of these
processes to the intensity and time course of
therapeutic and toxicology effects of drug. It
describes the processes whereby a drug
administered by a specific mode and in a specific
dose is handled by the body, leading to specific
drug concentrations in different tissues/organs.
Part of drug will reach site(s) of action and
exert its pharmacodynamic action. - Another way it can be said as what body does to
drug. - Pharmacokinetics is used in the clinical setting
to enhance the safe and effective therapeutic
management of the individual patient. This
application has been termed as Clinical
Pharmacokinetics
5Application of Pharmacokinetics
- Drug Development
- Clinical Pharmacy
- Deciding Dosage Regimen
- Deciding Rational Dose, Frequency And Duration
- Formulation Development
- Rational Drug Design (QSPKR)
- ADME Study, Bioavailability Or Bioequivalence
Studies - In Vitro In Vivo Correlation Studies
- Pharmacokinetics Pharmacodynamics Relationship.
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7Phamacokinetic Parameters
- Overall first order elimination rate constant (K)
- Half life ( t ½ )
- Clearance (Total, Renal, Hepatic, etc.) (Cl)
- Effective concentration range
- Absorption rate constant ( Ka )
- Extent of bioavailability ( F )
- Fraction of dose excreted unchanged in urine (
Xu8 ) - Blood plasma concentration ratio
- Apparent volume of distribution ( Vd )
- Fraction of protein binding (Fb)
- Peak concentration (Cp)
- Time to reach peak concentration (tp )
- Toxic concentrations
8Drug in Urine
K4
K5
Ka
Drug at Absorption site
Drug in Blood
Metabolite(s)
K6
Drug in Other Excretory Fluids
K1
K-1
K2
K-2
K3
Drug in Tissues
Drug in Other Fluids of Distribution
K-3
Schematic representation of drug absorption,
distribution, and elimination
9ADME CHARACTERS
- Absorption Absorption is defined as the process
by which unchanged proceeds from site of
administration to site of measurement within the
body. - Absorption is not restricted to oral
administration. It occurs as well following
intramuscular, subcutaneous, and other
extravascular routes of administration.
Monitoring intact drug in blood or plasma offers
a useful means of assessing the entry of drug
into the systemic circulation. - There are several possible sites of loss. GI
lumen, liver, muscle, tissues (sites of
administration). - The loss as drug passes, for the first time,
through sites of elimination, such as the GI
membranes and the liver, during absorption is
termed as first-pass effect. -
10ADME CHARACTERS
- Distribution The transfer of drug from blood to
extravascular fluids (i.e., extra-cellular and
intracellular water) and tissues is called
distribution. Drug distribution is usually a
rapid and reversible process. - Drug in the plasma exists in a distribution
equilibrium with drug in the erythrocytes, in
other body fluids and in tissues. Changes of
plasma drug concentration are indicative of
changes in drug level in other tissues including
sites of pharmacologic effect.
11- Metabolism It is the biochemical (enzymatic)
conversion of a drug to another chemical form. - Many tissues in the body are capable of
metabolizing drugs, but most drugs are mainly
metabolized in the liver by enzymes localized in
hepatic microsomes. - Drug-metabolizing enzymes oxidize, reduce,
hydrolyze, or conjugate compounds. Reduction,
oxidation, and hydrolytic reactions (phase I
pathways) result in metabolites with functional
groups (hydroxyl, amine, or carboxyl) that can be
conjugated (phase II). - In man the most common conjugation of drugs
or metabolites occur with acetate, sulfate,
glycine, or glucuronic acid.
12ADME CHARACTERS
- Elimination It is the irreversible loss of drug
from the site of measurement. - The transfer of drug from the blood to the
urine or other excretory compartments (i.e.,
bile, saliva, sweat, milk, etc.) and the
enzymatic or biochemical transformation of drug
in the issues or plasma to metabolic products,
are usually irreversible processes. The net
result of these irreversible steps is called drug
elimination. - Elimination occurs by two processes ,
excretion and metabolism. Elimination processes
are responsible for the physical or biochemical
removal of drug from the body
13 Excretion It is the irreversible loss of
chemically unchanged drug by various routes. This
can occur through urine, biliary secretion,
saliva, sweat, milk, respiratory route.
Routes of excretion and extent of excretion by
any route may vary from drug to drug depending on
nature and physicochemical properties of
drugs.
14Factors Influence Drug Absorption
- Biological Factors
- Physicochemical Factors
- Formulation Factors
15Biological Factors
- Gastrointestinal Physiology
- Anatomy GIT
- Gastrointestinal Blood Flow
- Gastrointestinal pH
- Gastric Emptying and Gastrointestinal Motility
- GIT Contents acids, enzymes, mucin, bile salts
- Effects of Food/Diet on Drug Absorption
- Presence of other drugs
- Routes of administration
16Physicochemical Factors
- Drugs pKa and Gastrointestinal pH
- Lipid solubility and Partition coefficient
- Dissolution and pH
- Diffusion Layer pH
- Salts
- Soluble Prodrugs
- Surface area and particle size
- Crystal form
- Drugs stability at site of absorption
- Complexation
- Adsorption
- Viscosity
17Formulation Factors
- Dosage Forms
- Solutions
- Suspensions
- Capsules
- Tablets
- Coated Tablets
- Enteric-coated Tablets
- CR formulations
- Targeted or site specific formulaitons
18Distribution
- Drug Distribution encompasses
- Distribution in Blood and other fluids
- Cellular Distribution
- Drug Penetration in CNS
- Placental Transfer of Drugs
- Blood Flow
- It is expressed by Distribution Volumes (Vd)
- Drug binding at different places is very
important - Drug Binding in Blood
- Plasma protein binding and drug distribution
- Plasma protein binding and drug effect
- Plasma protein binding and elimination
- Drug Binding in Tissues
- For designing novel delivery systems knowledge of
distribution characters is very important and
useful.
19Factors Affecting Metabolism
- Genetic Variation
- Environmental Determinants
- Inhibition of drug metabolism
- Induction of drug metabolism
- Disease
- Age and Sex
- Body Weight and Size
- Obesity
- Pregnancy
20Excretion
- Drug Excretion
- Renal Excretion
- Glomerular filtration, Tubular secretion,
Tubular reabsorption - Renal Clearance
- Biliary Excretion
- Salivary Excretion
- Secretion of drugs into milk
- Other excretion
21Pharmacokinetic characterization of drugs for
selection of suitable delivery systems
- compartment model
- elimination rate constant or terminal half-life(t
½) - Area under the concentration-time curve(AUC)
- Total clearance (ClT)
- Apparent volume of distribution (Vd)
- Mean steady state concentration (Css)
- Mean residence time
- First-pass effect
- Intrinsic absorption rate constant
- Relative areas
- Dosage form index
-
22Important biopharmaceutical characters of drug
for developing delivery system
- Molecular weight
- pKa
- Isoelectric point
- Solubility
- Apparent partition coefficient
- Extent of protein binding
- Extent of a1 acid glycoprotein binding
- Erythrocyte uptake
- General absorbability
- Biopharmaceutical aspects for route of
administration
23Design of Controlled Release formulation
- CT is the target concentration to be maintained
for T hr - Rate of Elimination K. CT.Vd or 0.693
CT.Vd - t1/2
- Where K is elimination rate constant of the drug
- Vd is apparent volume of distribution .
- Rate of absorption, Ka.Xa should be equal to rate
of elimination to maintain constant
concentration. So, - Ka. Xa K. CT. Vd
- Then rate of release should be equal to rate of
absorption and rate of elimination. So - rate of release, Kr K. CT.Vd
24- So,
- Maintenance dose rate of release x
duration to be maintained - K. CT. Vd.T
- tmax 2.303 Log Ka
- Ka-K
K - where Ka is absorption rate constant
- Loading dose CT.V eKtmax
- F
- where F is bioavailability (fraction)
- P.S Above is on the basis that drug confers one
compartment - distribution.
25- Equation to express plasma concentration of CR
product administered - C Ko (e-KT-1)e-Kt
- VK
- Where Ko is Zero order release rate
- T is time of total release
- t is anytime at which concentration is
measured. - t can b less than or equal or more than T
26Site specific Delivery
kLOCAL
kLOCAL
k1
k13
k31
k31
k13
kinput
kEL
k2
P-D
Elimination
k12
k21
k12
k21
k3
Scheme 3
27Drug Targeting
Chemical Coupling
Reduction
(D-QC)
(D-DHC)
(D) (QC)
BBB
(D-DHC)- BRAIN
(D-DHC)
CIRCULATORY SYSTEM AND ORGANS
Oxidation
Oxidation
Enzymatic cleavage
(D-QC) BRAIN
(D-QC) CIRCULATORY SYSTEM
K3
K3
(D) (QC)
(D) (QC)
K1
K2
BBB
Elimination
K4
28Important Considerations
- Ideally, drug delivery systems should be
designed on the basis of a knowledge of the
desired time-profile of drug response. - It is important to establish the relationship
between in vivo and in vitro profiles (IVIVC) in
order to optimize the formulation and for quality
control purposes. - These objectives require a reliable method for
estimating the rate of bioavailability of the
drug from the delivery system.
29Pharmacokinetics Evaluation of Novel Delivery
Systems in vivo.
- The in-vivo evaluation of delivery devices
involves two basic questions - Is the desired rate-time profile of release as
shown in vitro actually obtained in vivo? - Is the desired response-time profile obtained
in-vivo? - To answer the first, four approaches are there
- Assay of unreleased drug.
- Assay of parent drug and/or metabolite in blood,
plasma, or serum. - Assay of parent drug and/or metabolite in
excreta - Quantity of response intensity.
30- Second question can be answered if
pharmacological or - clinical response can be quantified directly
(like blood - pressure, dilation of pupils, intraocular
pressure, urinary - output, electrolyte excretion, blood glucose
levels, etc). - Otherwise long range clinical studies are
required. - The selection or choise of a suitable method for
estimating drug input rate and pharmacodynamic
effect is very important.
31Pharmacokinetic Consideration of Site- Specific
Drug Delivery Systems
- Objective of drug targeting is to deli er a drug
to its site of action and at the same time,
minimize any toxic effects. In pharmacokinetic
terms, it aims to maximize the ratio of drug
concentration at its site of action to that at
site of potential toxicity. - The evaluation can be done by
- - Steady state analysis
- - Pharmacodynamic aspects
- - Temporal aspects
32Steady state analysis
Qr
S
R
T
Qt
Drug targeting index (DTI)
AUCR/AUCT (drug carrier admin.)
DTI ------------------
AUCR/AUCT (drug admin.)
AUC is area under the concentration time profile
33Pharmacodynamic aspects
AUIT (drug administration)
Target Index, TI --------
AUIT (drug carrier admins.)
AUI
stands for area under the intensity-time
profile Temporal aspects
MIR/MIT(drug carrier adm) MI (Max.
Intensity) --------------
MIR/MIT(drug adm)
34Conclusion
- It is very important to have complete knowledge
of pharmacokinetic characters of drug and factors
affecting them to have complete knowledge/study
for designing an effective and useful drug
delivery systems. - Pharmacokinetic study is also important to
identify variables that are important in
determining the potential success of drug
delivery systems. - It can be used to evaluate the products or
delivery systems - Selection/design of proper experimental protocol
is very important. Suitable analytical method is
necessary for proper estimation. - IV-IV correlation and PK/PD relationship are also
useful tool for better design. -
35 Suggested References1.
Pharmacokinetics M.Gibaldi and D. Perrier,
Marcel Dekker Inc. USA 2nd edition 1982.2.
Novel Drug Delivery Eds. L.F.Prescott and
W.S.Nimmo John Wiley Sons UK 1989.3. Drug
Delivery Devices Fundamentals and Applications
Ed. P.Tyle Marcel Dekker Inc. USA 1988.4.
Biopharmaceutics and Clinical Pharmacokinetics
M. Gibaldi Lee and Febiger USA, 4th edition
1991.5. Modern Pharmaceutics Eds. G.S.Banker
and C.T.Rhodes Marcel Dekker Inc.USA 3rd
edition 1996.6. Pharmaceutical Bioequivalence
Eds. P.G.Welling, F.L.S. Tse and S.V.Dighe
Marcel Dekker Inc.USA 1991. 7. Novel Drug
Delivery Systems Ed. Y.W.Chien, Marcel Dekker
Inc.USA 2nd edition, 1992
36Thanks