10/10/2019

Pharmacokinetics
Lecture1: Introduction to Pharmacokinetics

Dr. Khaled Almansour

Asst. Professor
Department of Pharmaceutics
University of Hail, KSA
k.f.a.almansour@gmail.com

Lecture learning objectives

• Define Pharmacokinetics.

• Learn the meaning of dosage regimen/ How to design it.

• Understand and use plasma concentration v.s time profile (curve)

to define:
-Pharmacokinetics (PK) parameters.
-Pharmacodynamics (PD) parameters.

• The concept of variability and how it relates to PK/PD.

• PK/PD characteristics of different sites of drug administration:

-Intravascular routes.
-Extravascular routes.

• Pharmacokinetic Models:
-Compartment model.
-physiological model.

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Introduction

Medicines development journey- overview

• Drug discovery and development.

• Regulatory agencies.
• Clinical trials. Phases I to IV.
• Orphan drug.
• Generic formulations.
• Bioavailability. Bioequivalence.

Introduction

Evaluation of drug performance: a major requirement for

drug approval by drug agencies.

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Introduction

Pharmacokinetics (PK) is the study of kinetics of

absorption, distribution, metabolism and
excretion/elimination (ADME) of drugs and their
corresponding pharmacologic, therapeutic, or toxic
responses in man and animals.

• Theoretical aspect: Involves development of

pharmacokinetic models to predict drug disposition.

• Experimental aspect: Involves development of

biological sampling techniques, analytical methods for
measurement of drug concentration in biological
samples .

Introduction
• Duration of drug therapy ranges from a single dose (acute
condition) to drugs taken life-long (chronic conditions).

• The frequency of administration of a drug in a particular

dose is called Dosage regimen

• Depending upon the therapeutic objective , the duration

of drug therapy and the dosage regimen decided

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Applications of Pharmacokinetics

• Design of dosage regimen

• Dose adjustment in disease states

• Prediction of therapeutics response

• Measurement of bioavailability

• Evaluation of drug interactions (drug–drug interactions,

food–drug interactions, or chemical–drug interactions, such
as the interaction of a drug with tobacco).

Plasma Concentration versus Time Profile

• Relationship between the administered dose
and concentration of drug in plasma (amount
of drug in the body) over time.

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Plasma Concentration versus Time Profile

Two categories of parameters can be

evaluated from a plasma concentration time
profile

Pharmacokinetics (PK) parameters Pharmacodynamics (PD) parameters

“What the body does to the drug” “What the drug does to the body”

Site of
Dosage regimen Plasma Effects
action

Variability
Pharmacokinetics (PK) Pharmacodynamics (PD)
“What the body does to the drug” “What the drug does to the body”

Site of
Dosage regimen Plasma Effects
action

People differ in:

• Their responsiveness to a drug (therapeutic and

toxic effects)
• The way they “handle” drugs: absorption and
disposition.

Variability exists in both PK and PD.

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Variability in PK/PD

Absorption Site of
Dosage regimen Plasma
Distribution action
Concentration
Elimination

Dose
Dosage form
Route of administration

Drug interaction:
Patient Disease
[Drug /Food/Natural products]

Variability in PK/PD

Dosage regimen Site of

Plasma action Effects
(Dose/frequency)

• Therapeutic effect.
Depend on the concentration of drug
• Toxic effect. at the Site of action .

Corresponds to a specific Difficult to measure

concentration of drug in
plasma. Can be measured

Pharmacokinetics and Pharmacodynamics

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Pharmacodynamics
• Pharmacodynamics: The relationship between the drug
concentration at the site of action and pharmacologic
response/effect.
• A drug fails to elicit a therapeutic response when the drug
concentration is below the minimum effective concentration (MEC)
and cause toxic effects when above the maximum safety concentration
(MSC).

Pharmacodynamics

• Plasma drug concentration between these two limits is called as the

Therapeutic concentration range or Therapeutic window.

• Therapeutic index (TI): The ratio of MSC to MEC of the drug.

• TI is commonly used term to describe drug safety.

Plasma drug level within the therapeutic window = therapeutic success

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Pharmacodynamics
• When the difference between the MEC and the MSC is large, the
therapeutic window/ range will be referred to as Wide.
• When the difference between the MEC and the MSC is small, the
therapeutic window/index will be referred to as Narrow.

Wide therapeutic Narrow therapeutic

window/range window/range

Drug concentration
Drug concentration

MSC
MSC
(w/v)

(w/v)
MEC
MEC

Time (time unit) Time (time unit)

Pharmacodynamics

Drug Uses/Category Therapeutic

window/range
Aspirin Non-steroidal Wide
anti-
inflammatory
Most antibiotics Bacterial Wide
infections
Digoxin Cardiac Narrow
dysfunction

Vancomycin Penicillin- Narrow Severe toxicity

(Antibiotic) resistant and sometimes
infection irreversible

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Plasma Concentration versus Time Profile

Pharmacodynamic Parameters

μg/ mL
MSC

MEC

Pharmacodynamic Parameters

1- Minimum Effective Concentration (MEC)

Minimum concentration of drug in plasma required to
produce the therapeutic effect (reach the site of
action/receptor site). Concentration of drug below MEC is
said to be in the sub-therapeutic level

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Pharmacodynamic Parameters

2- Maximum safe concentration (MSC) / Minimum

toxic concentration (MTC)
Concentration of drug in plasma above which adverse or
unwanted effect are precipitated. Concentration above MSC
is said to be in the toxic level.

Pharmacodynamic Parameters
3- Onset of action/ Onset time: Beginning of pharmacological
response is onset of action & occurs when the plasma drug
concentration reach MEC.

4- Duration of action : The time period for which the plasma

concentration of drug remains above the MEC level.

5- Termination of action: The time point when the plasma

concentration of drug falls under the MEC level.

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Pharmacodynamic Parameters
6- Intensity of action : Maximum pharmacological response
produced by the peak plasma concentration of drug.

7- Therapeutic range : Drug concentration between MEC and

MSC represents the therapeutic range. It is also known as
therapeutic window.

Plasma Concentration versus Time Profile

Pharmacokinetic Parameters

Curve peak Elimination

phase
(w/v)
Absorption
phase

Absorption phase: The portion of the curve to the left of curve peak.
Elimination phase: The portion of the curve to the right of curve
peak.

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Pharmacokinetic Parameters
1- Maximum/Peak plasma concentration (Cmax)

• The point of maximum concentration of drug in

plasma.

• The peak concentration (Cmax) represents the point

where the absorption rate = the elimination rate of
drug.

Pharmacokinetic Parameters
• The peak concentration (Cmax) represents the point
where the absorption rate = the elimination rate of
drug.

Rate of drug
absorption
Cmax

Plasma

Rate of drug Rate of drug Rate of drug

Rate of drug
abs. > Rate of abs. = Rate of abs. < Rate of
elimination
drug elim. drug elim. drug elim.

Absorption phase Elimination phase

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Pharmacokinetic Parameters
1- Maximum/Peak plasma concentration (Cmax)

• Cmax is expressed in (w/v) e.g. (µg/ml).

• It depends upon:
- Administered dose.
- Rate of absorption.
- Rate of Elimination.

• Cmax is important for

pharmacological response,
Cmax should ideally be above
MEC but less than the MTC.

Pharmacokinetic Parameters
2- Time of Peak Concentration (tmax)
• The time for drug to reach Cmax.
• tmax is expressed in time units e.g. hours or days.
• Useful in estimating the rate of drug absorption
• Useful for assessing the efficacy of drugs used to treat
acute condition (headache).

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Pharmacokinetic Parameters
3- Area under the curve (AUC)
• Represents the total integrated area under the plasma
level-time profile.
• Expresses the total amount of drug that’s comes into
the systemic circulation.
• AUC is expressed in (w/v*time unit) e.g. µg/ml*hours.
• It is the most important parameter in evaluating the
bioavailability of a drug
from its dosage form as
it represents the extent of
absorption.

Other pharmacokinetic Parameters

Parameter Abbreviation
Volume of distribution Vd
Clearance Cl
Plasma concentration T1/2
half life
Elimination rate K

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Sites of drug administration

Sites of drug administration are classified into two categories:

• Intravascular routes

• Extravascular routes

1. Intravascular Routes

• Include intravenous and intra-arterial administration.

• The entire administered dose reaches the systemic

circulation.

• No absorption phase and has immediate onset of action

• This route is used more often in life-threatening situations.

• Adverse reactions are difficult to reverse or control;

accuracy in calculations and administration of drug dose,
are very critical.

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1. Intravascular Routes

• The value of Cmax is obtained mathematically, since

measurement of Cmax may not be possible due to improper
timing of the blood samples.

• Cmax can be estimated from the plasma drug concentration

v.s time by taking the intercept.

Plasma Concentration v.s Time Profile ( IV Bolus): Example

1. Intravascular Routes
Plasma Concentration v.s Time Profile
μg/ mL

Elimination phase
only

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2. Extravascular Routes

• Include oral, intramuscular (IM), subcutaneous (SC),

rectal, transdermal, and inhalation routes.

• The entire administered dose may not reach the systemic

circulation and produce pharmacological effects
(incomplete absorption).

• An absorption phase is present.

• The onset of action varies.

2. Extravascular Routes
Plasma Concentration v.s Time Profile

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Exemple 1
10 mg of Drug A was administered to a male patient (80 kg, 35 years old) orally.
Blood samples were taken at different times and the plasma concentrations of the
drug were measured. The table below shows the plasma concentrations measured
at different times after administration of the drug. Knowing that the therapeutic
window of Drug A is within 1-3 μg/ml, Define the following PK/PD parameters
Cmax, tmax and the onset of action. Based on the plasma drug level, Has the dose
given achieved therapeutic success?

MSC

MEC

Pharmacokinetic Models
A model is a hypothesis using mathematical terms to
describe quantitative relationships (experimental data).

These models simply use the experimental data and

allow an empirical formula to estimate the drug
concentration throughout the body & compute
meaningful PK parameters.
From previous example

Cmax
Vd=?

Cl=?

tmax

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1- Compartment Models (Empirical model)

Compartment model assumptions:

1- The body is represented as a series of compartments, which

communicate reversibly with each other.

One Compartment

2- Each compartment is not a real (physiological/anatomical) but a

fictitious or virtual & considered as a tissue or group of tissues that have
similar drug distribution characteristics (similar blood flow and drug
affinity).

1- Compartment Models
Models assumptions:
3- Within each compartment, the drug is considered to be rapidly and
uniformly distributed, so that the drug concentration represents an
average concentration.

4- Rate constants k are used to represent rate of entry into and exit from
the compartment.
Rate of Compartment 1 Rate of
entry k exit k

5- The selection of a model depends upon the distribution

characteristics of a drug and the route of drug administration.
6- The slower the drug distribution and elimination, regardless of the
route of administration, the greater the number of compartments.
7- The model is an open system because drug can be eliminated from the
system.

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1- Compartment Models
Pharmacokinetic models are used to:

1. Predict plasma, tissues, and urine drug levels.

2. Calculate the optimum dosage regimen for patients.

3. Estimate the possible accumulation of drugs and/or

metabolites.

4. Describe how changes in physiology or disease affect the

absorption, distribution, or elimination of the drug.

1- Compartment Models
Types compartmental models

• One-Compartment Open Model: This model assumes that the

drug can enter or leave the body (the model is "open"), and the
body acts like a single and uniform compartment.

• Multicompartment Models: The body acts as

multicompartment (different tissues) where the drug generally
distributes unevenly in these compartments.

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1- Compartment Models

Elimination
Central or First Peripheral or Second
Compartment Compartment
Absorption

Central compartment Peripheral compartment

• Plasma, extracellular fluid, and highly • Deeper tissues, tissues with lower
blood perfused tissues (e.g: liver, lungs). blood perfusion.
• Distribution takes some time.
• Instantaneous distribution.
• Called: second compartment
• Called: first compartment

1- Compartment Models
Model 1

• One compartment open model, IV injection

No
absorption
Rate of elimination

The entire body

Model 2

• One compartment open model, extravascular routes (oral,

intramuscular, etc)

Rate of absorption Rate of elimination

The entire body

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1- Compartment Models
Model 3

• Two compartment open model, IV injection

Major organs Peripheral organs

No
absorption
Distribution rate
Rate of elimination
Model 2
Model 4
• Two compartment open model, extravascular routes (oral,
intramuscular, etc)
Major organs Peripheral organs
Rate of absorption

Rate of elimination Distribution rate

1- Compartment Models
Recognizing number of compartments from the
drug plasma concentration v.s time curve:

• Look for deflection in the curve: elimination phase.

50
100 2 compartments
40
C (mg/L)

30
 phase
C (mg/L)

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10
10
 phase
0
0.0 2.5 5.0 7.5 10.0
Time (h) 0.0 2.5 5.0 7.5 10.0
Time (h)

 phase or distribution phase

 phase or terminal phase or elimination phase

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2- Physiological Models (realistic model)

These models are also known as
physiologically-based pharmacokinetic models
(PBPK models).

• They are drawn on the basis of known anatomical and

physiological data and thus present a more realistic
picture of drug disposition in various organs and
tissues.

Summary

• Pharmacokinetics: - Theoretical aspect

- Experimental aspect
• Dosage regimen.

• Plasma Concentration v.s Time profile (curve):

-Pharmacokinetics (PK) parameters “What the body does to the drug”
-Pharmacodynamics (PD) parameters “What the drug does to the body”

• The concept of variability in both PK/PD.

• Application of PK/PD:
-Intravascular routes.
-Extravascular routes.

• Pharmacokinetic Models:
-Compartment model (Empirical model)
-physiological model (realistic model)

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Normal graph paper (Cartesian)

10 mg of Drug A was administered to a male patient (80 kg, 35 years old) orally.
Blood samples were taken at different times and the plasma concentrations of the
drug were measured. The table below shows the plasma concentrations measured
at different times after administration of the drug. Knowing that the therapeutic
window of Drug A is within 1-3 μg/ml, Define the following PK/PD parameters
Cmax, tmax and the onset of action. Based on the plasma drug level, Has the dose
given achieved therapeutic success?

1- Cmax= 2.5 μg/ml

2- tmax= 5 h MSC

3- onset of action = 1.5 h

4- yes, because Cmax value is
MEC
within the therapeutic
window/range.

Normal graph paper (Cartesian)

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Exemple
Data from previous example

Define the following PK/PD parameters Cmax, tmax and the onset of action. Based
on the plasma drug level, Has the dose given achieved therapeutic success?

Homework
Plasma samples from a patient were collected after an oral dose of 10 mg of a
drug. Knowing that the drug was 80% absorbed and the therapeutic window
of the drug is with in 15-25 ng/mL sketch the plasma concentration v.s time
Curve. On the graph paper determine the following:
Time (h) 0.25 0.5 0.75 1 2 4 6 10 14 20
C(ng/mL) 2.85 5.43 7.75 9.84 16.2 22.15 23.01 19.09 13.9 7.97

1. Locate the absorption and elimination phases.

2. Define the Cmax, tmax, the onset of action, the termination of action and
the duration of action.
3. Estimate the drug bioavailability.
4. Determine whether the dose given achieved therapeutic success?

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