SEMINAR%20ON%20NONCOMPARTMENTAL%20PHARMACOKINETICS

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SEMINAR ON NONCOMPARTMENTAL PHARMACOKINETICS

• Presented by
• Ch. Karthik Siva Chaitanya
• M.Pharm (1st sem),Pharmaceutics
• UCPSc,KU.

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Contents

• Introduction to noncompartmental pharmacokinetic
  approach
• Differences between compartment and
  noncompartment models
• Concepts of noncompartmental model
• Statistical moments theory-Mean residence time
• Different pharmacokinetic parameters in
  noncompartment model

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• Noncompartment pharmacokinetics is a new approach
  devised to study the time course of drug in the
  body with out assuming any compartment model.
• Based on the statistical moment theory.
• Model independent method
• Overcomes some of the drawbacks
  associated with
• classical compartment modeling.
• Basic assumption is that drug or
  metabolite follows
• first-order kinetics.

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Noncompartment and Compartment models
Comparison
Compartment models Noncompartment models
These require elaborate assumptions to fit the data Do not require assumptions to compartment model.
Curve fitting of experimental data using computers. It is a tedious method. Simple algebraic equations. No curve fitting and no computers
Applicable to linear and nonlinear pharmacokinetics Applicable to linear pharmacokinetics.
C1 - time profile is regarded as expressions of exponents C1 time profile is regarded as statistical distribution.
These are useful for most of the situations, though assumptions of modeling are involved. Particularly useful for the applications of clinical pharmacokinetics, bioavailability, and bioequivalence studies.
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Advantages

• Derivation of PK parameters is easy, because of
  simple algebraic equations
• Mathematical treatment remains same, for drug or
  metabolite, provided elimination follows first
  order kinetics
• Drug disposition kinetics need not be described
  in detail

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Disadvantages

• Information regarding plasma drug
  concentration-time profile is expressed as an
  average
• Generally not useful for describing the time
  course of drug in the blood
• It is applicable only for linear pharmacokinetics

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Statistical Moment Theory

• Statistical moment A mathematical description of
  a discrete distribution of data.
• Statistical moments calculated from a set of
  concentration-time data represent an estimate of
  the true moment (or the true probability density
  function (PDF)that describes the true
  relationship between concentration and time).
• Statistical moment theory provides a unique way
  to study time-related changes in macroscopic
  events.
• Assume the drug molecules are eliminated
  according to a kinetic function, f(t) C 0e kt

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Eq.1
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AUC0? ? C dt
1
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AUMC0? ? t x C. dt
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I.V. bolus injection Calculation of AUC and
AUMC
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Mean residence time(MRT)

• The term mean residence time (MRT) describes the
  average time for all the drug molecules to reside
  in the body.

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MRT represents the time for 63.2 of drug
eliminated when given i.v. bolus injection.It
is analogous to plasma elimination half life,
t1/2, i.e., 50 elimination.Like half life, MRT
is a function of both distribution and
eliminationFor i.v bolus dose
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• In noncompartmental terms,
• k is constant equal to ratio of clearance to
  Vss
• Vss is volume of distribution at steady state
• 
  t1/2 0.693MRT
• MRTiv is used for comparison. For eg following
• constant rate of infusion
• Where T duration of infusion

0.693 Plasma elimination half
life t1/2 k10
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DRUG ABSORPTION

• MAT(Mean absorption time) is defined as the
  differences in mean residence time (MRT) after
  different modesof administration.
• MAT MRTni MRTiv
• MRTni mean residence time of drug by non-
• instantaneous route, h
• MRTiv mean residence time of drug by i.v.
• bolus injection
• Same equation is used for i.m. injection

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When absorption follows zero order
T time over which absorption takes place, h
MAT can be used for comparision of dosage forms
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OTHER APPLICATIONS OF MRT

• Mean Dissolution Time(MDT)
• MDTMRTtest-MRTsoln
• In oral administration,
• MRToralMRTiv1/Ka
• For evaluation of absorption data,
• MATMRTtest-MRTiv
  
• MAT1/Ka
• Ka is first order
  absorption rate constant
• 
  

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Drug Clearance

• After iv bolus administration,

• At steady state after constant rate iv infusion

Ko is rate of infusion Css is steady state
concentration

• By using extraction ratio
  ClQ(ER)

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APPARENTVOLUME OF DISTRIBUTION

• Vss is volume of distribution at steady
  state independent of elimination
• Vss i.v dose(AUMC)/(AUC)
• If drug is given by constant rate i.v infusion
• Where Ko is infusion rate is duration
  of infusion

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Steady State Plasma Drug Concentration

• The Css is a function of the effective rateof
  dosing and total body clearance of thedrug in a
  patient

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AUCss is AUC from t0 to t during a
dosinginterval at steady state
F is fraction bioavailable

• Method of superposition is used for predicting
  steady state
• concentration on repetitive dosing from data
  obtained
• after a single dose.

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Predicting the Time to Steady State

• Time required for the drug to reach steady state,
  i.e., 99, takes 6.65 half lives.
• In extravascular route (or prolongedrelease drug
  products), the time requiredto attain ss takes
  longer than predicted bybiological half life
• In multicompartment disposition, timerequired to
  attain to ss is shorter than that predicted by
  terminal half life

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In noncompartmentmodels, when the drug
isadministered repetitive dosing, fss
AUC area under the curve in single dose
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Bioavailability

• Bioavailability refers to the fractional dose of
  a dosage form reaches systemic circulation.
• For i.v. bolus injection, bioavailability is
  referred as unity (1)
• Bioavailability (F) of a dosage form

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Fraction metabolised

• AUCx1
• Fraction metabolized, Fm AUC1
• AUCx1 is area under the curve of metabolite
  concentrationin plasma versus time from zero to
  infinity
• AUC1 is the total area under the metabolite
  concentration time curve after a equimolar
  intravenous dose of a metabolite

Ch.Karthik SivaChaitanya,M.Pharm 1st Sem,UCPSc,KU
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CONCLUSION

• The noncompartmental pharmacokinetic methods
  permit a comprehensive pharmacokinetic analysis
  with out resort to curve fitting,sophisticated
  computers or tedious mathematical equations.
• Although these methods cannot be applied to all
  pharmacokinetic problems,they are useful for most
  problems and are particularly useful for the
  clinical application of pharmacokinetics.

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References

• Milo Gibaldi , Biopharmaceutics and clinical
  pharmacokinetics, 4th edition ,pg no 17-26
• D.Perrier,M.Gibaldi Pharmacokinetics, 2nd edition
  ,
• pg no 409-417
• Leon Shargel ,Applied biopharmaceutics and
  pharmacokinetics,5th edition,pg no 717-753
• V.Venkateshwarlu,Biopharmaceutics and
  pharmacokinetics, pg no 309-330
• www.pharainfo.net

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