PHARMACOKINETIC

MODELS
 OVERVIE
W
• Basic considerations in pharmacokinetics
• Compartment models
• One compartment model
• Assumptions
• Intravenous bolus administration
• Intravenous infusion
 BASIC CONSIDERATIONS IN
PHARMACOKINETICS
• Pharmacokinetic parameters
• Pharmacodynamic parameters
• Zero, first order & mixed order kinetic
• Rates and orders of kinetics
• Plasma drug conc. Time profiles
• Compartmental models – physiological model
• Applications of pharmacokinetics
• Non compartment model
 Common units in Pharmacokinetics
S.no Pharmacokinetic parameter Abbreviation Fundamental units Units example
1. Area under the curve AUC Concentration x time µg x hr/mL
2. Total body clearance ClT Volume x time Litres/time
3. Renal clearance ClR Volume x time Litres/time
4. Hepatic clearance ClH Volume x time Litres/time
5. Apparent volume of distribution VD Volume Litres
6. Vol. of distribution at steady state VSS Volume Litres
7. Peak plasma drug concentration CMAX Concentration mg/L
8. Plasma drug concentration CP Concentration mg/L
9. Steady-state drug concentration Css Concentration mg/L
10. Time for peak drug concentration TMAX Time Hr
11. Dose DO Mass mg
12. Loading dose DL Mass mg
13. Maintenance dose DM Mass mg
14. Amount of drug in the body DB Mass Mg
15. Rate of drug infusion R Mass/time mg/hr
16. First order rate constant for drug absorption Ka 1/time 1/hr
17. Zero order rate constant for drug absorption KO Mass/time mg/hr
18. First order rate constant for drug elimination K 1/time 1/hr
19. Elimination half-life t Time hr
A TYPICAL PLASMA DRUG CONC. AND TIME CURVE

8
 PHARMACOKINETIC
PARAMETERS
Three important parameters useful in assessing the bioavailability of a drug
from its formulation are:
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.
2. Time of peak concentration (tmax )
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 ).
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).
 PHARMACODYNAMIC
PARAMETERS
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
3. Onset time
Time required 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
 CONCEPT OF “HALF LIFE”
 ½ Life = how much time it takes for blood levels of drug to decrease to
half
of what it was at equilibrium
 There are really two kinds of ½ life…
 “Distribution” ½ life = when plasma levels fall to half what they were
at equilibrium due to distribution to/storage in body’s tissue reservoirs.
 “Elimination” ½ life = when plasma levels fall to half what they
were at equilibrium due to drug being metabolized and eliminated.
 It is usually the elimination ½ life that is used to determine dosing
schedules, to decide when it is safe to put patients on a new drug.
PHARMACOKINETIC MODELS AND COMPARTMENTS
 Pharmacokinetic Modelling

Compartmen Non-Compartment Physiologic

t Models Models
Models

AUC, MRT, MAT, Cl, VSS

Caternary Mamillary
Model Model

One compt Multi compt Two compt

iv
bolus i v bolus
Single oral
Dose
iv
infusion Oral
Intermittent i v infusion
drug
Multiple
 PHARMACOKINETIC MODELS
 Means of expressing mathematically or quantitatively, time course of drug
through out the body and compute meaningful pharmacokinetic parameters.
Useful in :
• Characterize the behavior of drug in patient.
• Predicting conc. Of drug in various body fluids with dosage regimen.
• Calculating optimum dosage regimen for individual patient.
• Evaluating bioequivalence between different formulation.
• Explaining drug interaction.
Pharmacokinetic models are hypothetical structures that are used to describe the
fate of a drug in a biological system following its administration.
Model
• Mathematical representation of the data.
• It is just hypothetical
 WHY MODEL THE DATA ?

There are three main reasons due to which the data is subjected to modelling.
1. Descriptive: to describe the drug kinetics in a simple way.
2. Predictive: to predict the time course of the drug after multiple dosing
based on single dose data, to predict the absorption profile of the drug
from the iv data.
3. Explanatory: to explain unclear observations.
 PHARMACOKINETIC
MODELING IS
USEFUL IN :-
• Prediction of drug concentration in plasma/ tissue/ urine at any point of
time.
• Determination of optimum dosage regimen for each patient.
• Estimation of the possible accumulation of drugs/ metabolites.
• Quantitative assessment of the effect of disease on drug’s adme.
• Correlation of drug concentration with pharmacological activity.
• Evaluation of bioequivalence.
• Understanding of d/i.
 COMPARTMENTAL MODELS
• A compartment is not a real physiological or anatomic region
but an imaginary or hypothetical one consisting of tissue/
group of tissues with similar blood flow & affinity.
• Our body is considered as composed of several
compartments connected reversibly with each other.
 ADVANTAGES
• Gives visual representation of various rate processes involved in
drug disposition.
• Possible to derive equations describing drug concentration changes in
each compartment.
• One can estimate the amount of drug in any compartment of the
system after
drug is introduced into a given compartment.
DISADVANTAGES
• Drug given by IV route may behave according to single compartment
model
but the same drug given by oral route may show 2 compartment
behaviour.
• The type of compartment behaviour i.E. Type of compartment model
may change with the route of administration.
 TYPES OF
COMPARTMENT
1. Central compartment
Blood & highly perfused tissues such as heart, kidney, lungs, liver, etc.
2. Peripheral compartment
Poorly per fused tissues such as fat, bone, etc.
MODELS:
“OPEN” and “CLOSED” models:
• The term “open” itself mean that, the administered drug dose is removed from
body by an excretory mechanism ( for most drugs, organs of excretion of drug is
kidney)
• If the drug is not removed from the body then model refers as “closed” model.
 ONE COMPARTMENT MODEL
 One compartment model can be defined :
• One com. Open model – i.V. Bolus.
• One com. Open model - cont. Intravenous infusion.
• One com. Open model - extra vas. Administration (zero-order
absorption)
• One com. Open model - extra vas. Administration (First-order
absorption )
• INTRAVENOUS (IV) BOLUS ADMINISTRATION
 RATE OF DRUG PRESENTATION TO BODY
IS:
• Dx/dt =rate in (availability)–rate out( Eli)

• Since rate in or absorption is absent, equation

becomes dx/dt = - rate out
• If rate out or elimination follows first order kinetic
Dx/dt = -kex (eq.1)
ELIMINATION PHASE:
 Elimination phase has three parameters:
• Elimination rate constant
• Elimination half life
• Clearance
 ELIMINATION RATE CONSTANT
• Integration of equation (1)
• In x = ln xo – ke t
Xo (eq.2)
= amt of drug injected at time t = zero i.E. Initial amount of drug injected
X=xo e-ket ( eq.3)
• Log x= log xo – ke t
2.303 (eq.4)

• Since it is difficult to directly determine amount of drug in body x, we use relationship

that exists between drug conc. In plasma C and X; thus
• X = vd C (eq. 5)
• So equation-8 becomes
log c = log co –
ke t 2.303 (eq.6)
KE = KE + KM +KB +KL +….. (Eq.7)
(KE is overall elimination rate constant)
 ELIMINATION HALF LIFE

T1/2 = 0.693
KE

(eq.8)
• Elimination half life can be readily obtained from the graph of log
c versus t
• Half life is a secondary parameter that depends upon the primary
parameters such as clearance and volume of distribution.
• T1/2 = 0.693 V d
Cl T (eq.9)
 APPARENTVOLUME OF
DISTRIBUTION
• Defined as volume of fluid in which drug appears to be
distributed.
• Vd = amount of drug in the body x
= Plasma drug concentration C (eq.10)

Vd = xo/co
=I.V.Bolus dose/co
(eq.11)
• Vol.
Example: 30=mg
Of dist. i.V. Bolus, plasma conc.= 0.732
30mg/0.732mcg/ml mcg/ml.
=30000mcg/0.732mcg/ml
= 41 liter.
• For drugs given as i.V.Bolus,
Vd (area)=xo/KE.Auc …….12.A
• For drugs admins. Extra. Vas.
Vd (area)=f xo/ke.Auc ……..12.B
 CLEARANCE
Clearance = rate of elimination
Plasma drug conc.. (Or) cl= dx /dt

C ……., (eq.13)
Thus, renal clearance = rate of elimination by
kidney
C
Hepatic clearance =
rate of elimination by
liver
Other organ clearance = rate of eliminationCby organ

C
Total body clearance:
Clt = clr + clh + clother ……, (eq.14)
• According to earlier definition
cl = dx /dt
C
• Submitting eq.1 dx/dt = KE X , above eq. Becomes ,clt = KE X/ C .., (Eq
15)
• By incorporating equation 1 and equation for vol. Of dist. ( Vd= X/C ) we can
get
clt =KE vd (eq.16)
• Parallel equations can be written for renal and hepatic clearance.
Cl =km vd
h (eq.17)

Clr =ke vd (eq.18)

• But, KE= 0.693/t1/2

• So, clt = 0.693 (eq.19)

vd
t1/2
• For non compartmental method which follows one
compartmental kinetic is :
• For drug given by i.V. Bolus

clt = xo
Auc
…..20.A
• For drug administered by e.V.
Clt = f xo …..20.B
Auc
• For drug given by i.V. Bolus
renal clearance = xu∞ …….(eq. 21)

auc
 ORGAN CLEARANCE
• Rate of elimination by organ= rate of presentation to the organ – rate of
exit from the organ.

• Rate of elimination =Q. Cin- Q.Cout

(Rate of extraction) =Q (cin-
cout)
Clorgan=rate of extraction/cin
=Q.Er …………….(eq 22)
=Q(cin-cout)/cin
• Extraction ratio:
ER= (cin- cout)/ cin
• ER is an index of how efficiently the eliminating organ clear the
blood
flowing through it of drug.
 According to ER, drugs can be classified as
• Drugs with high ER (above 0.7)
• Drugs with intermediate ER (between 0.7-0.3)
• Drugs with low ER (below 0.3)

• The fraction of drug that escapes removal by organ is expressed

as F= 1- ER
• Where f=systemic availability when the eliminating organ is liver.
 HEPATIC CLEARANCE

For some drugs,

The non renal clearance is equal to hepatic clearance.
Clh = clt – clr
 Can also be written down from eq 22
ClH= QH ERH
 QH= hepatic blood flow (1.5 L/min).
 ERH = hepatic extraction ratio.
 Hepatic clearance of drug can be divided into two groups :
 HEPATIC CLEARANCE
1. Drugs with hepatic blood flow rate-limited clearance
When ERH is one
ClH approaches its maximum value i.e hepatic blood flow.
ClH= QH
• Hepatic clearance said to be perfusion rate limited/ flow
dependent.
• Alteration in hepatic blood flow affects elimination of
drugs with high ERH
Example: Propanolol, Lidocaine
(Removed from blood as they are presented to the liver)
 HEPATIC CLEARANCE

Hepatic blood flow has very little/no effect on drug with low
ERH

Whatever concentration of drug present in the blood perfuses

liver, is always more than what the liver can eliminate (low first
pass hepatic metabolism)

Ex: Theophylline
HEPATIC BLOOD FLOW
 2. INTRINSIC CAPACITY
CLEARANCE
• Denoted as Clint, it is defined as the

“Inherent ability of an organ to irreversibly remove a

drug in the absence of any flow limitation."
• Depends on enzyme activity.

• Drugs with low ERH and with elimination primarily

by metabolism are greatly affected by changes in
enzyme activity.
• Hepatic clearance of such drugs is said to be
capacity limited.

Example: Theophylline
INTRINSIC CAPACITY CLEARANCE
ONE COMPARTMENT OPEN MODEL:
INTRAVENOUS INFUSION
• Model can be represent as : ( i.v infusion)

Drug R0 Blood & other KE

Zero order Body
Infusion tissues
rate

Dx/dt =Ro-kex …eq 23

X=Ro/ke(1-e-ket) …eq 24
Since X =vdc
C= Ro/kevd(1-e-ket) …eq 25

= Ro/clt(1-e-ket) …eq
26
• At steady state. The rate of change of amount of drug in the body is zero ,eq
23 becomes
Zero=Ro-kexss …27
Kexss=Ro …28
Css=Ro/kevd …29

=Ro/Clt i.e infusion rate ....30

Clearance
Substituting eq. 30 in eq.
26 …31
• C=Cs
s (1-e-ket) ...32
Rearrangement
C yields:
ss
• [Css-c]=e-ket . = -ket …33
Log CSS-C
2.303
Css
• If n is the no. Of half lives passed since the start of infusion(t/t1/2)
• Eq. Can be written as

• C=CSS [1-(1/2)n] …34

 INFUSION PLUS LOADING
DOSE

…35
XO,L=CSSVD Equation for computing the loading dose X0,L
 INFUSION PLUS LOADING
DOSE
SUBSTITUTION OF CSS=RO/KEVD form eq 29
XO,L=RO/KE …36

C=XO,L/VD E-KET+ RO/KEVD(1-E-KET)…37