Introduction

Drug-body interactions include

◼ Pharmacokinetics (PK)
The study of rate processes involved in absorption,
distribution, metabolism and excretion (ADME). In other
words it is the study of the time course of drug ADME.
It refers to relationship between conc. of the drug in the
plasma and the time (conc.-time profile).
◼ Pharmacodynamics (PD)

It refers to the relationship between drug concentration at

the site of action and the resulting effect.
“What the drug does to the body”
PK-PD
◼ Biopharmaceutics:
Biopharmaceutics considers the interrelationship
between PCPs of the drug, the DFs of the drug, rout
of administration on the rate and extent of systemic
abs.
• Minimum effective concentration (MEC):
The minimum concentration of drug needed at the
receptors to produce the desired pharmacologic effect.

• Minimum toxic concentration (MTC):

The drug concentration needed to just produce a toxic
effect.

• Onset time:
The time required for the drug to reach the MEC.

• Duration of action:
The difference between the onset time and the time for
the drug to decline back to the MEC.
What is the AIM of PK ???
The major goal is to design and to optimize a
dosing regimen with a maximal efficacy and
minimal toxicity, or to achieve a therapeutic
success regimen.
12
Plasma Concentration

10 TOXIC RANGE

6 THERAPEUTIC RANGE

2 SUB-THERAPEUTIC

0
0 1 2 3 4 5 6 7 8 9
Dose
◼ Accumulation:
the increase of drug concentration in blood and
tissues upon multiple dosing until steady state
is reached.
◼ Steady state:

The level of drug accumulation in the blood

and tissues upon multiple dosing when input
and output are at equilibrium. The steady state
drug concentrations fluctuate between a
maximum and a minimum steady state levels.
Therapeutic drug monitoring (TDM)
◼ Its importance appears when we are talking about
narrow therapeutic indices drugs,,, these drugs need
frequent monitoring of plasma drug conc., this done by
taking periodic blood samples. So it is the tool that can
guide clinical pharmacokinetic to provide effective and
safe drug therapy.
◼ Ex/ some drugs that need monitoring include:
Aminoglycosides, anticonvulsant, anticoagulants and
drugs used in chemotherapy.
◼ Clinical pharmacokinetics (CPK) is the application of
pharmacokinetic principles to the safe and effective
therapeutic management of drugs in an individual
patient.
 Absorption – Distribution – Metabolism -
Excretion

ABSORPTION

DISTRIBUTION
i.v

ELIMINATION
 Absorption
◼ Absorption is defined as the net transfer of
drug from the site of absorption into the
circulating fluids of the body.
◼ crossing the epithelium of the GI
membrane either by transcellular or
paracellular pathways.
◼ passing through the hepatoportal system
◼ If the drug is metabolized prior to reaching
systemic circulation, it is said to have
undergone first-pass metabolism.
 Absorption
◼ Factors affecting abs:
• Physico-chemical properties of the drug (M
wt., pKa, hydrophobicity, solubility,
polymorphism …..etc)
• Route of administration
• GI motility and GI transit time
• pH variability through GIT
• Drug food interaction (chelation….)
Bioavailability F
It is defined as the rate and extent to which the
active ingredient or active moiety is absorbed
from a drug product and becomes available at
the biophase (the site of action).
Some defined it as the fraction of the a mount of
unchanged drug that reach the systemic
circulation from the rout of administration.
Area under the curve (AUC):
obtained from the plasma concentration vs time
plot gives a measure of the amount of drug
absorbed systemically.
Distribution
◼ Drug distribution means the reversible
transfer of drug from one location to another
within the body.
◼ Once a drug has entered the vascular system
it becomes distributed throughout the various
tissues and body fluids in a pattern that
reflects the physico-chemical nature of the
drug and the ease with which it penetrates
different membranes.
 Distribution
◼ Factors affecting drug distribution:
◼ Rate of distribution:
• Membrane permeability of organ and tissues
• Blood perfusion
◼ Extent of distribution:
• Lipid solubility
• pH-pKa (pH-partition theory for ionizable
molecules)
• Plasma protein binding
• Intracellular binding
 Fluid Compartments

Pl
Tr
a
a
s
ISF, n The 60-40-20 Rule:
40% x 70 kg = 28 L water m
10 L s, 60 % of body weight is
a,
1 water
3-
L 40% of body weight is
4L
intracellular fluids
20% of body weight is
extracellular fluid

Extracellula
Intracellular Water =40%
r=20%

Total Body Water = 60% of weight (42 L)

Elimination
◼ Metabolism
Metabolism is the bioconversion of drug to
another chemical from or metabolite. mostly by
endogenous enzyme systems involving phase I
reactions. Such as oxidation (often by the
cytochrome P-450 system), reduction.
hydrolysis, or dealkylation, or by phase II
reactions, such as acetylation, sulfation, or
glucuronidation.
Elimination
◼ Excretion
Excretion is the removal of drug from the body
primarily via urine and occasionally via
feces, bile sweat, or exhaled air.
Renal
glomerular filtration
tubular reabsorption
tubular secretion
Rate and orders of PK process:
Rate means velocity or speed
◼ Rate constant: is the factor that determines the

rate of the process.

The rate const. is dependent on the order of the
process
◼ The order of the process: determine how the

amount of drug involved in the process will

influence the rate of the process. So it refers to
the way in which the concentration of drugs
influence the rate of a chemical reaction or
process
Rate and orders of PK process:
◼Zero order kinetics.
The rate of zero order is constant regardless the
amount or conc. of the drug (fixed amount loss
over fixed period of time).

Ethanol at therapeutic
level has zero order kinetics
◼First order kinetics
The rate is proportional to amount of drugs
available for the process.
Rate and orders of PK process:
Zero order First order
Rate and orders of PK process:
Nonlinear PK
At least one of the PK processes (ADME) is
saturable.
The PK parameters (t1/2, Vd, Cl) are conc.
dependent. Thus, it is termed also as dose-
dependent PK
We have partial or complete saturation for
receptor or enzymes.
Ex/ for drugs that obey the non-linear PK
(pheytoin, salicylate, and thiophylline)
 Linear PK Nonlinear PK
1-Known as dose-independent or 1-Known as dose-dependent or
concentration-independent PK. concentraton-dependent PK.

2-The absorption, distribution 2-At least one of the PK processes

and elimination of the drug (absorption, distribution or
follows first-order kinetics elimination) is saturable.

3-The PK parameters such as the 3-The PK such as the half-life,

half-life, total body clearance and total body clearance and volume
volume of distribution are of distribution are conc-
constant and do not depend on dependent.
the drug conc.

4-The change in drug dose results 4-The change in drug dose

in proportional change in the results in more than proportional
drug conc or less than proportional change
in the drug conc.
Key PK parameters:
1. Half-life (t1/2):
The time required for the amount or the conc. of
the drug in the body to decrease by one-half
2. Apparent volume of distribution (Vd)
Vd is the factor that relates the amount of drug in
the body to the plasma conc. at the same time. It
measures the extent of distribution of drug, so it is
only a mathematical expression and
theoretically calculated value.
Key PK parameters:
3. Total body clearance (TBC, Cl)
The process of removing a drug from plasma
and can be defined as the volume of plasma or
blood that is completely cleared from the drug
per unit time.
Unit of Cl is volume/time
It reflects the efficiency of irreversible
elimination of drug from the body.
Clearance relates the rate of elimination and
the plasma drug concentration.
4. Area under the curve (AUC)
Pharmacokinetic Modeling
◼ PK model
A model is a hypothesis using mathematical terms
to describe quantitative relationships concisely. The
predictive capability of a model lies in the proper
selection and development of mathematical
function(s) that parameterize the essential factors
governing the kinetic process. Therefore, it is a
mathematical model used to describe the drug
conc. in the body as a function of time.
The goal of PK data analysis is to estimate the PK
parameters that determine the rate of drug ADME,
these parameters needs assuming a certain PK
model.
Pharmacokinetic Modeling
◼ Why modeling??
1. Predict plasma, tissue, and urine drug levels with any dosage
regimen
2. Calculate the optimum dosage regimen for each patient
individually
3. Estimate the possible accumulation of drugs and/or
metabolites
4. Correlate drug concentrations with pharmacologic or
toxicologic activity
5. Evaluate differences in the rate or extent of availability
between formulations (bioequivalence)
6. Describe how changes in physiology or disease affect the
absorption, distribution, or elimination of the drug
7. Explain drug interactions
Modeling Approaches:
Several approaches have tried to model the relationship between
plasma conc. and the time.
1. Compartmental approach "mechanistic model"
The body is assumed to be made up of one or more
compartments, "no relation with anatomy".
Tissues of same compartment have the same blood flow and drug
perfusion
2.Physiological model
Modeling based on anatomical and physiological values, each
organ represents a single compartment, it is based on blood flow
rates through the organ or tissue
It is very difficult to validate a model in animals and impossible in
human, extensively used in anticancer compounds
3.Model-independent PK "non compartmental PK"
Less complex approach based purely on mathematical description
and calculation of PK parameters without assuming any model.
Pharmacokinetic Modeling
Compartmental PK
Compartmental PK
Model assumptions
1. Not Physiologic or anatomic region
2. For the tissue to be considered in one
compartment, the tissue or the group of tissues
should have similar blood perfusion rate and
drug affinity
3. Each compartment is Kinetically homogenized
dug dissolved in the compartment and uniformly
distributed (Rapid and quick mixing of drug in
the compartment)
4. Drug move in & out compartment
5. Model based on linear assumptions (first order
kinetics)
 1-Comp. Model 2-Comp. Model
Linear relationship between amount Curvilinear relationship between
and time on semilog paper amount and time on semilog paper
The linear relationship on a semilog The curve on a semilog paper
paper is called monoexponential indicates that the decline is due to
decline, the decline is due to only more than one exponential process
elimination i.e. distribution and elimination

Apparently there is no distribution

phase (the basic assumption for one
compartment model) the drug
immediately distributed to all parts of First the distribution is greater than
the body within a very short period elimination then equilibrium
of time, accordingly the equilibrium achieved and finally elimination only
is reached quickly and therefore we
were not able to see the distribution
phase
Physiologic PK model