Pharmacokinetics

Submitted By
Under the Guidance of
Dr. Sanjiv Kumar Chaudhri Shivangi Verma
Associate Professor M.PHARM Semester-2
Faculty of Pharmacy ( Pharmaceutics )
BBDNIIT Lucknow
 PHARMACOKINETICS
Pharmacokinetics is defined as the kinetics of drug ADME & their relationship with
pharmacological, therapeutic or toxicological response in man & animals.

Two Aspects of Pharmacokinetic Studies

Experimental Aspect Theoretical Aspect

Involve development of biological PK models to predict drug
sampling tech., analytical methods disposition after it's administration.
for measurement of drug &
metabolites concentration in
biological samples.
PLASMA DRUG CONCENTRATION – TIME PROFILE
Two categories of parameters can be evaluated from a plasma concentration
time profile :-
PHARMACOKINETIC PARAMETERS PHARMACODYNAMIC PARAMETERS
Peak plasma concentration ( Cmax) Minimum effective concentration (MEC)
Time of peak concentration (tmax) Maximum safe concentration (MSC)
Area under curve (AUC) Onset action
Onset time
Duration of action
Intensity of action
Therapeutic range
Therapeutic Index
PLASMA DRUG CONCENTRATION – TIME PROFILE
RATE, RATE CONSTANT & ORDER OF REACTION
• The velocity with which a reaction occurs is called as rate.
• Rate Constant :- The rate of reaction when the concentration of each reactant in
the reaction is unity.
• Order of reaction :- Sum of the Concentration of each reactant.

Consider the following chemical reaction - Drug A ------> Drug B

Rate of forward reaction is expressed as -
Negative sign indicates concentration of drug A decrease with time t.
If C is the concentration of drug A, then
•ʠ
• =-K
• K = Rate Constant
• n = Order of reaction.
ZERO - ORDER KINETICS
In zero order kinetics rate is constant and independent of the Concentration of any of reactant.
=-
If n = 0 = -= -
where = Zero order rate constant
= ---------------------------(1)
Rearranging the above equation
dc = -dt ------------------------(2)
Integrating equation (2)
=-
C = -+
C= -
= concentration of drug at t = 0
C = concentration of drug at time t
HALF LIFE

C= -
C = and t =
Put these values in equation (1)
= -
- = -
- = =
=
FIRST ORDER KINETICS

Rate is directly proportional to concentration of drug undergoing reaction.

= -K………….. (1)
Rearranging the equation (1)
= -K……………(2)
Integrating equation (2)
= -K
In C – In = -Kt
= – ……………(3)
HALF LIFE
Substituting C = and t = in the following equation (3)

= -

=
 PHARMACOKINETIC MODEL

• Models are mathematical representation of data. It is hypothetical.

• Goal is to estimate the Pharmacokinetic parameters that determines the rates of drug
ADME.
• Pk models used to
Predict plasma, tissue, urine drug levels with any dosage regimen.
Estimate possible accumulation of drugs.
To correlate drug concentration with pharmacologic & toxicologic activities.
Estimate different formulation of bioequivalence can be find out.
 To explain the drug interactions.
PHARMACOKINETIC MODELS

Pharmacokinetic Models

Compartment Model Non- Compartment Analysis Physiological Model

Mammillary Model

Caternary Model
MAMMILLARY MODEL

• Consist of one Central Compartment (Compartment 1) comprises of plasma and highly

perfused tissues such as lungs, liver, kidneys, etc.
• Elimination always occurs from the central compartment.
• Also consist of peripheral compartment (denoted by 2, 3, etc.) are those with low vascularity
& poor perfusion.
• Movement of drug between compartment is defined by characteristic first order rate constant
denoted by letter K.
• No. of rate Constants is given by R
• For intravenous administration R = 2n-1
• For extravascular administration R = 2n
 ONE COMPARTMENT OPEN MODEL i.v ONE COMPARTMENT OPEN MODEL ,
EXTRAVASCULAR ADMINISTRATION

𝐾 10 𝐾 01 𝐾 10
1 1

CATENARY MODEL

• The compartments are joined to one another in a series like compartments of a train.

𝐾 01 𝐾 12 𝐾 13
1 2 3
𝐾 21 𝐾 31
𝐾 10
PHYSIOLOGICAL MODELS
• Also known as Blood Flow or Perfusion Models.
• These models are based on known anatomic and physiologic data.
• The model considers that blood flow is responsible distributing drug to various parts of
the body.
• Organs/ tissues that have no drug penetration are excluded from consideration.
Example :- Bones.
 NONCOMPARTMENTAL ANALYSIS

• Also known as Model- Independent Method.

• It does not require the assumption of compartment.
• The non- compartmental approach, based on the statistical moments theory, involve
collection of experimental data following a single dose of drug.
MRT =
MRT= Mean Residence Time
AUMC= Area under the First- Moment Curve
AUC= Area under the Zero- Moment Curve
ONE-COMPARTMENT OPEN MODELS
 Assumptions :-
• Body is considered as a single unit that has no barriers to the movement of the drug.
• Final distribution equilibrium between drug in plasma and other body fluids is attained
instantaneously and maintained at all times.
• Drugs move dynamically in and out of this compartment.
• Elimination is a first order process
• Rate of input (absorption) > rate of output (elimination).
 The one compartment open model that describes the distribution & elimination after
an i.v bolus dose is:
k = Drug in body
IV , = Apparent volume of distribution
K = Elimination rate constant
Pharmacokinetics model for a drug
administered by rapid intravenous
injection.
ELIMINATION RATE CONSTANT

• The rate of elimination for most drug from the body is a first-order process.
• Rate of elimination depends on the concentration of drug present at that instance.
• The elimination rate constant K represented by the sum of metabolism and excretion.
• K= + -------------------------------(i)
• = first-order rate process of metabolism.
• = first-order rate process of excretion.
• The rate of elimination of drug in the body is 1st order process expressed as
= -K ---------------(ii)
K = Overall elimination rate constant
= Amount of drug in the body, remaining at any given time t
Integration of equation (ii)
= - + …………(iii)
where, = Drug in the body at time t
= Drug in body at t = 0
Semilog graph of the rate of drug elimination in a one compartment model -
𝐷 𝐵′
Drug in
Slope = -
body

Time
APPARENT VOLUME OF DISTRIBUTION, Vd

• The Volume of distribution represents a volume that must be considered in estimating

the amount of drug in the body from the concentration of drug found in the sampling
compartment.
• As does not have a true physiologic meaning in term of an anatomic space, the term
apparent volume of distribution is used.
• The Vd relates the concentration of drug in plasma () and the amount of drug in the
following equation = .
• Calculation of volume of distribution, Vd
• In a one compartment model (IV administration), the Vd is calculated, with following
equation
= = ---------------(1)

C°p = Determined by extrapolation, it represents the instantaneous drug concentration (at t=0)
after drug equilibrium in the body.
• Because both and are known at t = 0 , the may be calculated from equation (1)
• Semilog graph giving the value of by extrapolation.

𝐶 °𝑝
Plasma
Level
()

Time

From non - compartmental method -

=
Calculation of Vd from this equation is a model independent method because no
pharmacokinetic model is considered and AUC is determined directly by the trapezoidal rule.
• For each drug, the apparent is a constant.
• Extent of distribution of drugs are controlled by

Plasma Protein Binding

High Low

Small Large
(Ibuprofen) (Digoxin)
 CLEARANC
E
• Volume of plasma fluid i.e. cleared off drug per unit time. OR
• Fraction of drug removed per unit time.

CL= =

Total Body Clearance –

=+ +

The unit of clearance are ( , )

Clearance from non - compartmental method –

=
ONE-COMPARTMENT OPEN MODELS
INTRAVENOUS INFUSION

• In i.v infusion drug is infused slowly through a vein into the plasma at a constant or
zero - order rate.
• For drugs with a narrow therapeutic window (e.g - heparin), i.v infusion maintains an
effective constant plasma drug concentration by eliminating wide fluctuations between
the peak (maximum) & trough (minimum) plasma drug concentration.
• Plasma level-time curve for constant i.v infusion
• Because no drug was present in the body at zero time, drug level rises from zero drug
concentration & gradually becomes constant when a plateau or steady-state drug
concentration is reached.
At steady state, Rate of drug input = Rate of drug output
(infusion rate) (elimination rate)
So, rate of change in plasma drug concentration
=0
The change in amount of drug in the body at any time () during the infusion –
= Rate Input – Rate Output
= R – K --------------------(1)
= Amount of drug in the body , R = Infusion Rate (Zero Order), K = Elimination Rate Constant
(1st Order)
On integration of equation (1) and substitution of =
= (1-) .………………..(2)
As drug is infused , the value for time (t) increases in equation (2)
=0
 = ……………..(3)
At steady state when time is according to
=
= (Total Body Clearance)
= ……………..(4)

CALCULATION OF ELIMINATION HALF LIFE

= (1-)
We know that =
Putting these value in above equation :-
= (1-)
= Css -
= -
= ……………..(5)
Taking log
= - ……………..(6)
From the following graph elimination t1/2 is calculated

𝐶𝑆𝑆  − 𝐶𝑝
log( ) Slope = -
𝐶𝑆𝑆

Time
REFERENCE

• Shargel Leon, Pong Wu Susannal, Yu BC Andrew, " Applied Biopharmaceutics and

Pharmacokinetics", 5th edition, MC Graw hill, Page no - 42-46, 32-63, 108-112.
• Brahmankar D.M , Jaiswal B Sunil ,``Biopharmaceutics and pharmacokinetics ``,
Vallabh prakashan, page no-235 - 268