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Pharmacokinetics in Design of Novel Drug Delivery Systems By Prof' R' N' Saha BITS, Pilani, India

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Title: Pharmacokinetics in Design of Novel Drug Delivery Systems By Prof' R' N' Saha BITS, Pilani, India


1
Pharmacokinetics in Design of Novel Drug Delivery
Systems By Prof. R. N. Saha BITS, 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.

4
Pharmacokinetics
  • 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

5
Application 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.

6
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7
Phamacokinetic 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

8
Drug 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
9
ADME 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.

10
ADME 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.

12
ADME 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.
14
Factors Influence Drug Absorption
  • Biological Factors
  • Physicochemical Factors
  • Formulation Factors

15
Biological 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

16
Physicochemical 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

17
Formulation Factors
  • Dosage Forms
  • Solutions
  • Suspensions
  • Capsules
  • Tablets
  • Coated Tablets
  • Enteric-coated Tablets
  • CR formulations
  • Targeted or site specific formulaitons

18
Distribution
  • 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.

19
Factors Affecting Metabolism
  • Genetic Variation
  • Environmental Determinants
  • Inhibition of drug metabolism
  • Induction of drug metabolism
  • Disease
  • Age and Sex
  • Body Weight and Size
  • Obesity
  • Pregnancy

20
Excretion
  • Drug Excretion
  • Renal Excretion
  • Glomerular filtration, Tubular secretion,
    Tubular reabsorption
  • Renal Clearance
  • Biliary Excretion
  • Salivary Excretion
  • Secretion of drugs into milk
  • Other excretion

21
Pharmacokinetic 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

22
Important 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

23
Design 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

26
Site specific Delivery
kLOCAL
kLOCAL
k1
k13
k31
k31
k13
kinput
kEL
k2
P-D
Elimination
k12
k21
k12
k21
k3
Scheme 3
27
Drug 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
28
Important 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.

29
Pharmacokinetics 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.

31
Pharmacokinetic 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

32
Steady 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
33
Pharmacodynamic 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)

34
Conclusion
  • 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 References 1.
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
36
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