Pharmacokinetics

Biopharmaceutics

1. PHARMACOKINETICS
Prepared By
GirijeshKumar Pandey
M.Pharm. (Pharmaceutics)

2. Contents
•Pharmacokinetics: Definition
•Introduction to Pharmacokinetics,
•Compartment models,
•Non compartment models,
•Physiological models,
•One compartment open model.
(a) Intravenous Injection (Bolus)
(b) Intravenous infusion and
(c) Extra vascular administrations.
•Pharmacokinetics parameters -KE ,t1/2,Vd,AUC,Ka, Cltand
CLR-definitions methods of eliminations, understanding of
their significance and application

3. Pharmacokinetics: Definition
•Pharmacokineticsis defined as the kinetics of
drug absorption, distribution, metabolism and
excretion (KADME) and their relationship with
the pharmacological, therapeutic or
toxicological response in man and animals.

4. Introduction to Pharmacokinetics
•Pharmacokinetics, derived from the Greek
wordspharmakon(drug) andkinetikos(movement), is used to
describe the absorption, distribution, metabolism, and
excretion (ADME) of a compound.
•Pharmacokinetics provides a mathematical basis to assess the
time course of drugs and their effects in the body. It enables
the following processes to be quantified: ADME.
•These pharmacokinetic processes, often referred to as ADME,
determine the drug concentration in the body when
medicines are prescribed. A fundamental understanding of
these parameters is required to design an appropriate drug
regimen for a patient.

5. Introduction to Pharmacokinetics
•Pharmacokinetics is important because:
–a. The studies completed in laboratory animals may
give useful indications for drug research and
development. For example less powerful molecules in
vitro can turn out more effective in vivo because of
their favorablekinetics (greater absorption, better
distribution, etc.).
–b. Pharmacokinetics supports the studies of preclinical
toxicology in animals (toxicokinetics) because the drug
levels in plasma or tissues are often more predictive
than the dose to extrapolate the toxicity data to man.
Toxicokineticsis also important to:

6. Introduction to Pharmacokinetics
•verify that the animals have measurable levels of drug
in plasma and that these levels are proportional to the
administered dose,
•estimate the area under the curve and the maximum
concentration of the drug in plasma, because these
parameters can be used to represent the exposure of
the body to the drug,
•evidence differences in pharmacokinetics between the
various groups of treatment, the days of treatment and
other factors,
•estimate the variability between animals and identify
cases with abnormal levels of the drug.

7. Introduction to Pharmacokinetics
•c. Knowledge of the kinetics and of the effects
(pharmacodynamics) of drugs in man is necessary for a correct use
of drugs in therapy (choice of the best route of administration,
choice of the best dose regimen, dose individualization).
Figure: Relationship of pharmacokinetics and pharmacodynamicsand
factors that affect each.

8. Methods for Pharmacokinetics
Data Analysis

9. Compartmental model
•A compartment is a group of tissues with similar
blood flow and drug affinity. A compartment is
physiologic and anatomic region.
•Compartment is the traditional and most widely
used approach to pharmacokinetic
characterization of drug. These models simply
interpolate the instrumental data and allow on
empirical formula to estimate drug concentration
with time.

10. Compartmental model
Assumptions of compartmental models
•The body is represented as a series of
compartment arranged in series or parallel to
each other.
•The rate of drug movement between
compartment is described by first order kinetics.
•Rate constants are used to represent rate of entry
into and exit from compartment.
•A statistical analysis of plasma concentration time
data is another method used to find out no of
compartments.

11. Compartmental Model
Application Of Compartment Modelling
•i. It is simple and flexible approach and widely
used.
•ii. It gives a visual representation of various rate
process involved in drug disposition.
•iii. It is useful in predicting drug concentration
time profile in both normal and pathological
composition.
•iv. It is useful in relating plasma drug levels in
therapeutic and toxic levels.

12. Compartmental Model
•Depending upon whether the compartment
are arranged parallel or in series,
compartments models are divided into two
categories –
–Mammillary model
–Catenary model

13. Compartmental Model
•Mammillary model
–It consists of one or more peripheral
compartments connected to the central
compartment in a manner similar to connection of
satellites to a planet
–They are joined parallel to the central
compartment
–The central compartment comprises of plasma
and highly perfusedtissues such as lungs, liver,
kidney etc. which rapidly equilibrate with drugs.

14. Compartmental Model

15. Compartmental Model
•CatenaryModel
–The compartments are joined to one another in a
series like compartments of a train.
–It is rarely used because it is not observed that
anatomically or physiologically various organs are
directly linked to the blood compartment.

16. Compartmental Model
•Physiological Model
–They are drawn on the basis of known anatomical and
physiological data
–So it present more realistic picture of drug disposition
in various organs and tissues.
–Tissues with similar perfusion properties are grouped
into a single compartment
–e.g. lungs, liver, brain and kidney are grouped as
rapidly equilibrating tissues
–While muscles and adipose as slowly equilibrating
tissues.

17. Compartmental Model
•Physiological Model

18. Compartmental Model
•Distributed Parameter Model
–It is analogous to physiological model but has
been designed to take into account
–Variations in blood flow to an organ
–Variations in drug diffusion in an organ
–The distributed parameter model differ from
physiological model in that the mathematical
equation are more complex and collection of drug
concentration data is more difficult.

19. Non Compartment model
•Also known as model independent methods
•Because it does not require the assumption of
specific compartment model.
•This method is based on the assumption that the
drugs or metabolites follow linear kinetics,
•So this technique can be applied to any
compartment model.
•Based on statistical moments theory
•It involves collection of experimental data
following a single dose of drug

20. Non Compartment model
•If one consider the time course of drug
concentration in plasma as a statistical
distribution curve, then
MRT = AUMC / AUC
Where MRT= mean residence time AUMC= area under the first
moment curve AUC= Area under the zero moment curve
MRT= is defined as the average amount of time
spent by the drug in the body before being
eliminated.
AUMC and AUC can be calculated from the use of
trapezoidal rule

21. One Compartment Model
(Instantaneous Distribution Model)
•The time course of drug concentration determined
after the administration can satisfactorily explained by
assuming the body as a single well mixed compartment
with first order disposition process.
•The body is constituted as a single kinetically
homogeneous unit with no barriers to movement of
drug.
•Elimination is a first order process with first order rate
constant.
•Drug moves dynamically in and out of the
compartment then rate of input will be greater then
the rate of output.

22. One Compartment Model
One compartment “open model”
•The term open indicates that the input (availability)
and output (elimination) are unidirectional and that
the drug can be eliminated from the body.
•Classification of one compartment open model:
–Depending upon rate of input ,several one compartment
models are defined
•One compartment open model-intravenous bolus administration
•One compartment open model-continuous intravenous infusion
•One compartment open model-extra vascular zero –order
absorption
•One compartment open model-extra vascular first –order
absorption

23. One Compartment Model
•One compartment open model-intravenous bolus
administration
–When a drug that distributes in body is given in
the form of a lipid intravenous injections , its takes
about one or three minutes, for complete
circulation.
–The model can be diagrammatically depicted as

24. One Compartment Model
•It can be mathematically represented as :
•The general expression for rate of drug
presentation to the body is: on
•Since rate in or absorption is absent, the
equation becomes:

25. One Compartment Model
•If the rate out or elimination follows first-order
kinetics, then:
•Where, K
E= first-order elimination rate constant,
and X = amount of drug in the body at any time t
remaining to be eliminated.
•Negative sign indicates that the drug is being lost
from the body.

26. One Compartment Model
Estimation of Pharmacokinetic Parameters
•For a drug that follows one-compartment kinetics and
administered as rapid i.v. injection, the decline in
plasma drug concentration is only due to elimination of
drug from the body (and not due to distribution), the
phase being called as elimination phase.
•Elimination phase can be characterized by 3
parameters—
–1. Elimination rate constant
–2. Elimination half-life
–3. Clearance

27. One Compartment Model
–In figure (a) Cartesian plot of a drug that follows
one-compartment kinetics and given by rapid i.v.
injection, and (b) Semi logarithmic plot for the
rate of elimination in a one-compartment model.

28. One Compartment Model
•Elimination Half-Life:
–It is defined as the time taken for the amount of
drug in the body as well as plasma concentration
to decline by one-half or 50% its initial value.
•Apparent Volume of Distribution:

29. One Compartment Model
•Clearance
–Clearance is defined as the theoretical volume of body
fluid containing drug (i.e. that fraction of apparent
volume of distribution) from which the drug is
completely removed in a given period of time. It is
expressed in ml/min or liters/hour.
–The total body clearance, ClT, also called as total
systemic clearance, is an additive property of
individual organ clearances.

30. One Compartment Model
•One compartment open model-continuous
intravenous infusion
–Rapid i.v. injection is unsuitable when the drug has
potential to precipitate toxicity or when maintenance of a
stable concentration or amount of drug in the body is
desired.
–In such a situation, the drug (for example, several
antibiotics, theophylline, procainamide, etc.) is
administered at a constant rate (zero-order) by i.v.
infusion.
–In contrast to the short duration of infusion of an i.v. bolus
(few seconds), the duration of constant rate infusion is
usually much longer than the half-life of the drug.

31. One Compartment Model
•Advantages of zero-order infusion of drugs
include—
–1. Ease of control of rate of infusion to fit
individual patient needs.
–2. Prevents fluctuating maxima and minima (peak
and valley) plasma level, desired especially when
the drug has a narrow therapeutic index.
–3. Other drugs, electrolytes and nutrients can be
conveniently administered simultaneously by the
same infusion line in critically ill patients.

32. One Compartment Model
•The model can be represented as follows:
•Plasma concentration-time profile for a drug given by
constant rate i.v. infusion (the two curves indicate different
infusion rates Ro and 2Ro for the same drug)

33. One Compartment Model
•One compartment open model-extra vascular zero –
order absorption
–When a drug is administered by extravascularroute
(e.g. oral, i.m., rectal, etc.), absorption is a
prerequisite for its therapeutic activity.
–The rate of absorption may be described
mathematically as a zero-order or first-order process.
A large number of plasma concentrationtimeprofiles
can be described by a onecompartmentmodel with
first-order absorption and elimination. However,
under certain conditions, the absorption of some
drugs may be better described by assuming zero-order
(constant rate) kinetics.

34. One Compartment Model
–Distinction between zero-order and first-order
absorption processes. Figure a is regular plot, and
Figure b a semi log plot of amount of drug
remaining to be absorbed (ARA) versus time t.

35. One Compartment Model
•Zero-order absorption is characterized by a
constant rate of absorption

36. Pharmacokinetics Parameters

37. Pharmacokinetics Parameters
1.Peak plasma concentration ( Cmax)
•The point at which, maximum concentration
of drug in plasma.
•Units : µg/ml
•Peak conc. Related to the intensity of
pharmacological response, it should be
above MEC but less than MSC.
•The peak level depends on administered dose
and rate of absorption and elimination.

38. Pharmacokinetics Parameters
2. Time of peak concentration (t
max)
•The time for the drug to reach peak
concentration in plasma (after extra vascular
administration).
•Units : hrs
•Useful in estimating onset of action and rate of
absorption.
•Important in assessing the efficacy of single dose
drugs used to treat acute conditions (pain,
insomnia ).

39. Pharmacokinetics Parameters
3. Area under curve (AUC)
•It represents the total integrated area under the
plasma level-time profile and expresses the total
amount of the drug that comes into systemic
circulation after its administration.
•Units : µg/ml x hrs
•Represents extent of absorption –evaluating the
bioavailability of drug from its dosage form.
•Important for drugs administered repetitively for
treatment of chronic conditions (asthma or
epilepsy).

40. PharmacodynamicParameters
1. Minimum effective concentration (MEC)
Minimum concentration of drug in
plasma/receptor site required to produce
therapeutic effect.
•Concentration below MEC –sub therapeutic level
•Antibiotics -MEC
2. Maximum safe concentration (MSC)
Concentration in plasma above which adverse or
unwanted effects are precipitated.
•Concentration above MSC –toxic level

41. Pharmacodynamicparameters
3. Onset time Timerequired to start producing
pharmacological response. Time for plasma
concentration to reach MEC after administrating drug
4. Onset of action The beginning of pharmacologic
response. It occurs when plasma drug concentration
just exceeds the required MEC.
5. Duration of action The time period for which the
plasma concentration of drug remains above MEC
level.
6. Intensity of action It is the minimum pharmacologic
response produced by the peak plasma conc. Of drug.
7. Therapeutic range the drug conc. Between MEC and
MSC

42. References
•Biopharmaceuticsand Pharmacokinetics -A
treatise 2nd Edition by D. M. Brahmankarand
Sunil B. Jaiswal, VallabhPrakashan, New Delhi.
•https://www.pharmpress.com/files/docs/clinical_
pharmacokinetics_samplechapter.pdf
•R. Urso, P. Blardi, G. Giorgi, A short introduction
to pharmacokinetics, Europ. Rev. for Med. and
Pharmacol. Scs, 2002; 6: 33-44
•https://www.slideshare.net/sheetujha/one-
compartment-model-ppt