INTRODUCTION TO

BIOPHARMACEUTICS
AND
PHARMACOKINETICS
School of Pharmacy
Centro Escolar University
DEFINING THE NECESSARY

An Introduction to
Biopharmaceutics and
Pharmacokinetics
CHAPTER OBJECTIVES:
¨ Define drug product performance and biopharmaceutics.
¨ Describe how biopharmaceutics affects drug product
performance.
¨ Define pharmacokinetics and describe how pharmacokinetics
is related to pharmacodynamics and drug toxicity.
¨ Define the term clinical pharmacokinetics and explain how
clinical pharmacokinetics may be used to develop dosage
regimens for drugs in patients.
¨ Define pharmacokinetic model and list the assumptions that
are used in developing a pharmacokinetic model.
¨ Explain how the prescribing information or approved
labeling for a drug helps the practitioner to recommend an
appropriate dosage regimen for a patient.
What is a drug?

¨ DRUG
¤Substances intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of
disease
Local and Systemic Effect
¨ Local Effect
¤ Obtained when the drug product is administered at the site where the
pharmacological response is desired either by adsorption or penetration
¨ Systemic Effect
¤ Obtained when the drug released from the drug product enters the blood
and/or lymphatic streams and is distributed within the body-or at least
several organs-regardless of the site and route of administration
Dosage form (drug product)

¨ Considered to be drug delivery systems that release and

deliver drug to the site of action such that they produce
the desired effect
n Designed specifically to meet the patient’s needs including
palatability, convenience, and safety
Xenobiotics

¨ Foreign compounds exposed to the biological

system
Drug Product Performance

¨ Release of the drug substance from the drug

product either for local drug action or for drug
absorption into the plasma for systemic therapeutic
activity…
BIOPHARMACEUTICS
Biopharmaceutics

¨Provides the scientific basis for drug

product design and drug product
performance
Biopharmaceutics

¨ The examination of the interrelationship of the;

1. physical/chemical properties the drug;
2. the drug product (dosage form) in which the drug is given
and the;
3. route of administration
¨ on the rate and extent of systemic drug absorption
Biopharmaceutics

Physical / chemical
properties of a
drug (PC)

Rate and extent of

Dosage form (DF) Bioavailability
systemic drug
absorption

Route of
administration
(RoA)
 PC

RoA DF

Design of the Manufacture of

drug product Stability of the product
the drug
within the Rate of
Release of the drug product dissolution/
drug from the release of the
drug at the
drug product
absorption site

Rate and extent of

systemic drug absorption
Biopharmaceutics and designing drug products:
CONSIDERATIONS

¨ Therapeutic objective
¤ For rapid relief of symptoms, slow extended action, or chronic use
¤ For local or systemic action

¨ Drug (active pharmaceutical ingredient, API)

¤ Physicochemical properties (solubility, polymorphism, particle size)
Biopharmaceutics and designing drug products:
CONSIDERATIONS

¨ Route of administration
¤ Oral, topical, parenteral, inhalational, etc
¨ Drug dosage and dosage regimen
¤ Largeor small dose, frequency of doses, patient acceptance,
patient compliance
Biopharmaceutics and designing drug products:
CONSIDERATIONS

¨ Type of drug product

¤ Orally disintegrating, immediate release, extended release tablets
¤ Transdermal, topical, parenteral, implant, etc

¨ Excipients
¤ Affect drug release
¨ Method of manufacture
¤ Variables in manufacturing process, including weighing, blending,
release testing, sterility
PHARMACOKINETICS
A.D.M.E.
PHARMACOKINETICS

¨ The science of the kinetics of drug absorption,

distribution, and elimination (ie, metabolism
and excretion)
LADME processes can be divided into two classes;
drug input and drug output
Input processes are:

¨ L = Liberation
¤ the release of the drug from it's dosage form
¨ A = Absorption
¤ the movement of drug from the site of administration to the
blood circulation
¤ Is the process of uptake of the compound from the site of
administration into the systemic circulation
Output processes: Disposition of drugs

¨ D = Distribution
¨ Elimination

¤M = Metabolism
¤ E = Excretion
Drug Disposition

¨A term used to describe drug distribution

and elimination
DRUG DISPOSITION
Therefore…

¨ Drug disposition characterization is an important

prerequisite for determination or modification of
dosing regimens for individuals and groups of
patients.
Distribution

¨ The process by which drug diffuses or is transferred from

intravascular space to extravascular space (body tissues)
¨ Is the partitioning of drug molecules among numerous
locations in the body
Elimination

¨ Refers to the irreversible removal of drug from the body

by all routes of elimination (metabolism and excretion)
¨ Effect:

¤ Declinein plasma drug concentration observed after

systemic drug absorption
Metabolism (Biotransformation)

¨ Process by which the drug is chemically converted in the

body to a metabolite
¨ Usually an enzymatic process
Excretion

¨ Removal of intact drug

¨ Example:
¤ Nonvolatile drugs – excreted mainly by renal excretion
Pharmacokinetic studies
Involves:
¨ Experimental approach

¤ Development of biologic sampling techniques

¤ Analytical methods for the measurement of drugs and metabolites

¤ Procedures that facilitate data collection and manipulation

¨ Theoretical approach
¤ Development of pharmacokinetic models that predict drug disposition after
drug administration
CLINICAL PHARMACOKINETICS
The Application
Clinical pharmacokinetics

¨ The application of pharmacokinetic methods to drug

therapy

SIGNIFICANCE???
¨ Intra- and interindividual variations will frequently result in either a
subtherapeutic or toxic response which may then require adjustment to
the dosing regimen
Drug concentration vs Drug response

TOXIC

DRUG CONCENTRATION
POTENTIALLY TOXIC

THERAPEUTIC

POTENTIALLY SUBTHERAPEUTIC

SUBTHERAPEUTIC
PHARMACODYNAMICS
Pharmacodynamics

¨ Refers to the relationship between the drug

concentration at the site of action (receptor) and
pharmacologic response, including biochemical and
physiologic effects that influence the interaction of drug
with the receptor
Drug-receptor interaction

¨ Combining of a drug molecule with the receptor for

which it has affinity, and the initiation of a
pharmacologic response by its intrinsic activity
Pharmacokinetic-pharmacodynamic models
¨ Constructed to relate plasma drug level to drug concentration
at the site of action and establish the intensity and time course
of the drug
DRUG EXPOSURE AND DRUG RESPONSE
Drug Exposure and Drug Response

¨ Drug exposure
¤ Refersto the dose (drug input to the body) and various measures of
acute or integrated drug concentrations in plasma and other biological
fluid
¨ Drug response
¤ Refers to direct measure of the pharmacologic effect of the drug
Drug responses measured
¨ Clinically remote biomarkers
¤ Receptor occupancy
¨ Presumed mechanistic effect
¤ ACE inhibition
¨ Potential or accepted surrogate
¤ Effects on blood pressure, lipids, or cardiac output
¨ Full range of short-term or long-term clinical effects related to
either efficacy or safety
Toxicokinetics and Clinical Toxicology
Toxicokinetics
¨ Application of pharmacokinetic principles to the design, conduct,
and interpretation of drug safety evaluation studies and in
validating dose-related exposure in animals (eg., preclinical
drug development)
¨ Data obtained:

¤ Aids in interpretation of toxicologic findings in animals and extrapolation of

the resulting data to humans
Clinical toxicology

¨ The study of adverse effects of drugs and

toxic substances (poisons) in the body
Measurement of Drug Concentrations
Gathering pharmacokinetic data…
Question to ask…

Where do we obtain data regarding drug

concentrations?
Biologic samples

INVASIVE METHOD NONINVASIVE METHOD

¨ Blood ¨ Urine
¨ Spinal fluid ¨ Saliva
¨ Synovial fluid ¨ Feces
¨ Tissue biopsy Whole blood ¨ Expired air
Serum
Plasma
Whole blood

¨ Obtained by
¤ Venouspuncture and contains an anticoagulant such as
heparin or EDTA
¨ Components
¤ Whole blood contains all the cellular and protein elements of
blood
Serum

¨ Obtained from:
¤ Wholeblood after the blood is allowed to clot and the clot is
removed
¨ Components
¤ Serum does not contain the cellular elements, fibrinogen, or
the other clotting factors from the blood
Plasma
¨ The liquid supernatant
obtained after centrifugation
of non-clotted whole blood
that contains an
anticoagulant (heparin)
¨ Plasma is the noncellular
fraction of whole blood and
contains all the proteins
including albumin
Plasma
¨ Plasma perfuses all the tissues
of the body, including the
cellular elements in the blood
¨ Changes in the drug
concentration in plasma will
reflect changes in tissue drug
concentrations
Drug concentration in tissues
¨ Used to ascertain if the drug reached the tissues and reached
the proper concentration within the tissue.
Drug concentration in tissues

Disadvantages
¨ Drug concentration measurement difficult (because only a small
sample of tissue is removed)
¨ Drug concentrations in tissue biopsies may not reflect drug

concentration in other tissues nor the drug concentration in all

parts of the tissue from which the biopsy material was removed.
Drug concentration in urine and feces
Urine
¨ an indirect method to ascertain the bioavailability of a drug

¨ the rate and extent of drug excreted in the urine reflects the
rate and extent of systemic drug absorption
Drug concentration in urine and feces
Feces
¨ May reflect drug that has not been absorbed after an oral
dose
¨ May reflect drug that has been expelled by biliary secretion

after systemic absorption

¨ Fecal collection is performed to recover certain solid oral

dosage forms that do not dissolve in the gastrointestinal tract

but slowly leach out drug
Drug concentrations in saliva

¨ Saliva drug levels tend to approximate free drug

¤ Because only free drug diffuses into the saliva
¨ Saliva/plasma drug concentration ratio is mostly
influenced by the pKa of the drug and the pH of the
saliva
Drug concentrations in saliva

¨ Use of salivary drug concentrations as a

therapeutic indicator should be used with caution
and preferably as a secondary indicator
The Plasma Level – Time Curve
Plasma level – time curve

¨ Generated by obtaining the drug concentration in

plasma samples taken at various time intervals
after a drug product is administered
Plasma level – time curve
Consider the following data:
Plasma concentration
Time (hr)
of drug A (ug/mL)
0 12
1 10
2 8
3 6
4 4
5 2
Plasma level – time curve
14

Plasma concentration of drug A (ug/mL) 12

10

0
1 2 3 4 5 6

Time (hours)
Drug level – time curve and pharmacologic
parameters
¨ MEC
¤ reflects the minimum
concentration of drug
needed at the receptors to
produce the desired
pharmacologic effect
¨ MTC
¤ represents the drug
concentration needed to
just barely produce a toxic
effect
Drug level – time curve and pharmacologic
parameters
¨ Duration of action
¤the difference
between the onset
time and the time for
the drug to decline
back to the MEC
Drug level – time curve and pharmacologic
parameters
¨ Intensity (of pharmacologic
effect
¤ proportional to the number
of drug receptors occupied,
which is reflected in the
observation that higher
plasma drug concentrations
produce a greater
pharmacologic response, up
to a maximum
Drug level – time curve and pharmacologic
parameters

¨ Onset time
¤timerequired for the
drug to reach the
MEC.
Drug level – time curve
and pharmacokinetic parameter
¨ Peak plasma level
¨ A.k.a. maximum
drug concentration
¨ related to the dose,

the rate constant

for absorption, and
the elimination
constant of the
drug
Drug level – time curve and pharmacokinetic
parameter
¨ Time for peak
plasma level
¨ time of maximum
drug concentration
in the plasma
¨ a rough marker of
average rate of
drug absorption
Drug level – time curve
and pharmacokinetic parameter

¨ Area under the

curve (AUC)
¨ related to the
amount of drug
absorbed
systemically
Significance of Measuring Plasma Drug
Concentrations
Why is the plasma drug concentration measured?
Measuring plasma drug concentration

Concept 1
¨ Intensity of the pharmacologic or toxic effect of a drug is often
related to the concentration of the drug at the receptor site,
usually located in the tissue cells
Measuring plasma drug concentration

Concept 2
¨ most of the tissue cells are richly perfused with tissue fluids or
plasma

THEREFORE
¨ measuring the plasma drug level is a responsive method of

monitoring the course of therapy

Monitoring plasma drug concentrations

Concept 1
¨ Clinically, individual variations in the pharmacokinetics of drugs
are quite common
¤ Monitoring the concentration of drugs ascertains that the calculated dose
actually delivers the plasma level required for therapeutic effect
Monitoring plasma drug concentrations

Concept 2
¨ With some drugs, receptor expression and/or sensitivity in
individuals varies
¤ Monitoring of plasma levels is needed to distinguish the patient who is
receiving too much of a drug from the patient who is supersensitive to the
drug
Monitoring plasma drug concentrations

Concept 3
¨ A patient's physiologic functions may be affected by disease,
nutrition, environment, concurrent drug therapy, and other
factors
Monitoring plasma drug concentrations

Clinical uses:
1. Allows for the adjustment of the drug dosage in order to
individualize and optimize therapeutic drug regimens
Monitoring plasma drug concentrations

Clinical uses:
2. May provide a guide to the progress of the disease state and
enable the investigator to modify the drug dosage accordingly
in the presence of alteration in physiologic functions due to
disease
Drawbacks…
¨ Plasma drug levels are relatively useless for dosage
adjustment in the absence of pharmacokinetic information
¨ NEEDED PK INFO:

¤ TIME when the blood sample was drawn

¤ DOSE of the drug that was given

¤ ROUTE OF ADMINISTRATION
BASIC PHARMACOKINETICS AND PHARMACOKINETIC
MODELS
The complexity of drug treatment

Drug therapy regimen

¨ Estimation of drug dosing

¨ Prediction of the time course of drug efficacy for a given dose

“SO, WHAT MAKES DRUG TREATMENT

COMPLICATED?”
What makes drug treatment complicated?

¨Drugs are in dynamic state within the

body
What makes drug treatment complicated?

¨ As DRUGS move between TISSUES and FLUIDS:

¤Binds
with PLASMA or CELLULAR COMPONENTS
¤Metabolized
What makes drug treatment complicated?

¨ The biologic nature of drug distribution and

disposition is complex
¨ Drug events often happen simultaneously
What makes drug treatment complicated?
What makes drug treatment complicated?
Overcoming the complexities of drug treatment

¨ Simplifications of body processes are

necessary to predict a drug’s behavior in the
body.
Overcoming the complexities of drug treatment

¨ One way to make these simplifications is to apply

mathematical principles to the various processes.
Overcoming the complexities of drug treatment

¨ To apply mathematical principles, a model of

the body must be selected
MODELS
Mathematical (pharmacokinetic) models
Models

¨ A hypothesis using mathematical terms to

describe quantitative relationships concisely
Models

¨ 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
Related terminologies

¨ Variables
¤The experimental data (e.g., time, plasma drug
concentrations)
nINDEPENDENT VARIABLE
nDEPENDENT VARIABLE
Related terminologies

¨ Pharmacokinetic parameter
¤a constant for the drug that is estimated from the
experimental data (k – elimination rate constant)
Use of pharmacokinetic models

1. Predict plasma, tissue, and urine drug levels with any

dosage regimen
2. Calculate the optimum dosage regimen for each
patient individually
Use of pharmacokinetic models

3. Estimate the possible accumulation of drugs and/or

metabolites
4. Correlate drug concentrations with pharmacologic or
toxicologic activity
Use of pharmacokinetic models

5. Evaluate differences in the rate or the extent of

availability between formulations (bioequivalence)
6. Describe how changes in physiology or disease affect
the ADME of the drug
7. Explain drug interactions
TYPES OF MODELS

1. Empirical models
2. Physiologically based models
3. Compartmentally based models
Empirical models

¨ Simply interpolates the data

¨ Allows an empirical formula to estimate drug level
over time (only when limited information is
available)
Empirical models

¨ Practical but NOT USEFUL in explaining the

mechanism of the actual process by which the drug
is absorbed, distributed, and eliminated.
Physiologically based model

¨ Physiologic pharmacokinetics models (a.k.a.

Blood flow or perfusion models)
Physiologically based model

¨ PK models based on known anatomic and

physiologic data
¨ Potentially predict REALISTIC tissue drug
concentrations
¨ Info required is experimentally DIFFICULT TO
OBTAIN
COMPARTMENTALLY BASED MODELS
COMPARTMENT MODEL
¨ The body is represented as a single compartment or container for
some drugs.
¨ For other drugs a two or three compartment model is found to be
necessary
COMPARTMENT MODEL

¨ A compartment is NOT A REAL physiologic or anatomic

region but is considered a tissue or group of tissues that
have similar blood flow and drug affinity
COMPARTMENT MODEL

¨ Within each compartment, the drug is considered

uniformly distributed
¨ Mixing of the drug within a compartment is rapid
and homogenous
COMPARTMENT MODEL
TYPICAL ORGAN GROUPS

CENTRAL COMPARTMENT PERIPHERAL COMPARTMENT

¨ Heart ¨ Fat tissues

¨ Liver ¨ Muscle tissue
¨ Lungs ¨ Cerebrospinal fluid
¨ Kidneys
¨ Blood (plasma)
HIGHLY PERFUSED ORGANS POORLY PERFUSED
ORGANS
TYPES OF COMPARTMENT MODEL

1. Mammillary model
2. Catenary model
Mammillary model

¨ Most common compartment model used in

pharmacokinetics
MAMILLARY MODEL
MAMILLARY MODEL
MAMILLARY MODEL
One-compartment Model

¨ Drug is both added to and eliminated from a central

compartment
¨ The central compartment is assigned to represent plasma
and highly perfused tissues that rapidly equilibriate with
drug
One-compartment Model
¨ When an intravenous dose of drug is given, the drug enters directly
into the central compartment

¨ Elimination of drug occurs from the central compartment because the

organs involved in drug elimination (kidney and liver), are well-
perfused tissues
Two-compartment Model

¨ Drug can move between the central or plasma

compartment to and from the tissue compartment
¨ The total amount of drug in the body is simply the sum of
drug present in the central compartment plus the drug
present in the tissue compartment
Catenary model

¨ It is not used as often as the mammillary model since

it does not apply to the way most functional organs in
the body are directly connected to the plasma
CATENARY MODEL
END OF PRESENTATION
INTRODUCTION TO
BIOPHARMACEUTICS AND PHARMACOKINETICS
School of Pharmacy, Centro Escolar University