Biopharmaceutics and Clinical

Pharmacokinetics
Course No: 4103

Mohammad Mafruhi Sattar

Professor, Department of Pharmacy
Faculty of Biological Science
Jahangirnagar University
 COURSE OUTLINE
1. Introduction to Biopharmaceutics, Pharmacokinetics, Clinical
Pharmacokinetics.

Fundamental principles and concepts regarding

bioavailability, bioequivalence and chemical equivalence and
therapeutic equivalence. Importance of kinetic studies on
formulation development and clinical settings. Interpretations
through Exponents, Logarithms, Semi-logarithmic plotting,
Differential Calculus, Integral Calculus, Spreadsheet
Calculations and Spectrophotometric Analysis.
 COURSE OUTLINE (continued)

2. Drug absorption and distribution: (a) Passage of drugs

across biological barriers, i.e. passive diffusion, active
transport, facilitated diffusion and pinocytosis. (b) Factors
influencing absorption: Physicochemical, Pharmaceutical
and Physiological. (c) Drug distribution in the body, plasma
protein binding, significance of plasma protein binding,
determination of volume of distribution and its significance,
distribution co-efficient.
 COURSE OUTLINE (continued)
3. Bioavailability and Bioequivalence: Bioavailability
Parameters : Definitions and calculation of parameters (like
bioavailability factor, Cleanace values, Extraction ratio etc).
Bioavailability problems and probable solutions.
4. The concept of clearance: Mechanism of Renal and Hepatic
clearance, Factors affecting renal and hepatic clearance,
Clearance ratio and Extraction ratio, Determination of Renal
clearance and its ratio, Hepatic clearance and its ratio, Biliary
excretion and Extra-hepatic excretion.
 COURSE OUTLINE (continued)

5. Compartmental Kinetics: Compartmental models : definition

and scope

6. One Compartment Pharmacokinetic Model: Plasma data :

Area under the Curve and Half-life(bio). Pharmacokinetics of
drug absorption: Relevant methods for determining kinetic
order of absorption and rate constant(s). Methods of
determining Residual Back Feathering and Regression
procedure. Some practical citations of the techniques.
 COURSE OUTLINE (continued)
7. Multi-Compartment Pharmacokinetic Model: Multiple dosing:
Intravenous Continuous infusion relevant to Steady state Combined
Infusion and bolus administration, Combined slow and fast infusion post
administration. Multiple Intravenous and Single bolus administration.
Oral administration : Independent dosing and Multiple dosing.
Development of general equations for Cp(max), Cp(min) and
Cp(average). Development of general equation for Non-uniform dosing
intervals.
8. Non-linear pharmacokinetics with special reference to one
compartmental model after IV administration. Steady state saturation
principle and Michales Menten equation.
 COURSE OUTLINE (continued)
9. Clinical Pharmacokinetics: (a) Definition and scope
(b) Dose adjustment in patients with or without renal
and hepatic failure. (c) Design of single dose bio-
equivalence study and relevant statistics. (d)
Overview of regulatory and ethical requirements for
conduction of bioequivalent studies.
 References
• Leon Shargel and Andrew Yu, 2015. Applied
Biopharmaceutics & Pharmacokinetics,
Seventh Edition, McGraw Hill Companies
Inc.

• Gibaldi, Milo, 2005. Biopharmaceutics and

Clinical Pharmacokinetics, Fourth edition,
PharmaMed Press.
 References (continued)
• JS Kulkarni, Ap Pawar and VP
Shedbalkar, 2011. Biopharmaceutics
& Pharmacokinetics, CBS Publishers
and Distributors.
• Donald E. Cadwallader, 1983.
Biopharmaceutics and Drug
Interactions. Raven Press.
• Ashutosh Kar, 2010. Essentials of
Biopharmaceutics and
Pharmacokinetics, Reed Elsevier India
Pvt. Ltd
This book will be released on 3rd
December, 2021
 Introduction to Biopharmaceutics
• Pharmacokinetics, Clinical Pharmacokinetics and their role in formulation
development and clinical setting.
• Definitions (terms connected with the study of biopharmaceutics like
Bioavailability, bioequivalence and chemical equivalence, therapeutic
equivalence etc)
• historical development of the subject
• Fundamental principles and concepts
• Background Material:
• Exponents, Logarithms, Semi-log graph paper, Calculus, Differential
Calculus, Integral Calculus, Spreadsheet Calculations, Spectrophotometric
Analysis.
 Introduction to Biopharmaceutics (cont’d)

– Pharmacology
– Pharmacy
• Definition of
• Definition Pharmacology
• Branches of • Branches of
Pharmacy Pharmacology
• Evolution of
Pharmacy
– Biopharmaceutics
• Definition of
• Current and future
Biopharmaceutics
trend in pharmacy
• Drug Product
– Pharmaceutics – Invention (NDA, ANDA)
• Definition and scope – Brand drug product
of Pharmaceutics – Generic drug product
Introduction to Biopharmaceutics (cont’d)
3. Pharmacokinetic Introduction
– Pharmacokinetics
• Definition of Pharmacokinetics
• Pharmacokinetic Models
– Compartment Models
» Mammillary Model
» Catenary Model
– Physiologic Pharmacokinetic Model (Flow Model)
– Clinical Pharmacokinetics
– Pharmacodynamics
– Toxicokinetics and clinical Toxicology
– Measurement of drug concentrations
• Sampling of Biologic Specimens, Drug Concentrations in Blood,
Plasma, or Serum, Plasma Level–Time Curve, Drug Concentrations
in Tissues, Drug Concentrations in Urine and Feces, Drug
Concentrations in Saliva, Forensic Drug Measurements,
Significance of Measuring Plasma Drug Concentrations,
 Introduction to Biopharmaceutics (cont’d)

4. Background Material
– Exponents
– Logarithms
• Semi-log graph paper
– Calculus
• Differential Calculus
• Integral Calculus
– Spreadsheet Calculations
– Spectrophotometric Analysis
– Rates and orders of reactions
 Pharmacy
• The art or practice of preparing and preserving drugs,
and of compounding and dispensing medicines according
to prescriptions of physicians; the occupation of an
apothecary or a pharmaceutical chemist.
• A place where medicines are compounded; a drug store;
an apothecary's shop.
• The main purpose of this narrow field of education is to
develop an understanding of the properties of drugs and
medical products and their manufacture, control and use
in the community and hospitals.
 Biopharmaceutics
A study of the factors influencing the bioavailability and
disposition of drugs (how the physicochemical properties
of drugs, dosage forms and routes of administeration
affect the rate and extent of the drug absorption), and the
application of this information to optimise the therapeutic
usefulness of drugs in clinical practice. Particular emphasis
is placed on the clinical role of the Pharmacist in improving
the use of drugs through the practical application of
pharmacokinetics.
• Biopharmaceutics examines the interrelationship
of the physical/ chemical properties of the drug,
the dosage form (drug product) in which the drug
is given, and the route of administration on the
rate and extent of systemic drug absorption. The
importance of the drug substance and the drug
formulation on absorption, and in vivo distribution
of the drug to the site of action, is described as a
sequence of events that precede elicitation of a
drug’s therapeutic effect.
Biopharmaceutics: Integration of Physical /Chemical and
Biological/ Pharmacokinetic Principles and Impact on
Clinical Efficacy

• Biopharmaceutics has evolved into a broad-based discipline that

encompasses fundamental principles from basic scientific and
related disciplines, including chemistry, physiology, physics,
statistics, engineering, mathematics, microbiology, enzymology,
and cell biology. The biopharmaceutical scientist, therefore,
must have sufficient understanding of all of these scientific
fields in order to be most effective in a drug development role.
A scientist educated in the field of biopharmaceutics or
biopharmaceutical sciences could have expertise in a number of
interrelated specialty disciplines including formulation,
pharmacokinetics (PK), cell-based transport, drug delivery, or
physical pharmacy.
 Biopharmaceutics considers

• interrelationship of the physicochemical

properties of the drug
• dosage form in which the drug is given
• route of administration on the rate and
extent of systemic drug absorption.
 Biopharmaceutics involves factors that
influence the
(1) protection of the activity of the drug within
the drug product,
(2) the release of the drug from a drug product
(3) the rate of dissolution of the drug at the
absorption site
(4) the systemic absorption of the drug.
Scheme demonstrating the dynamic relationships
among the drug, the product, and pharmacologic
effect.
 Studies in biopharmaceutics use
in vitro “in the glass” in Latin, and refers to just that—when live
cells are removed from the organism and tested in an artificial,
controlled environment. An example would be growing cancer
cells in a dish outside of the body to study them and possible
treatments.
In vivo (Latin for “within the living”) is the study of the biological
effects of a drug in a complex living organism and is used to
observe the complex physiological effects of a drug. Examples can
include studies in animal models or human clinical trials.
In situ is a Latin phrase that translates literally to "on site" or "in
position." It can mean "locally", "on site", "on the premises", or
"in place" to describe where an event takes place and is used in
many different contexts.
in silico experiment is one performed on computer or via
computer simulation. The phrase is pseudo-Latin for "in silicon",
referring to silicon in computer chips.
 Physical Pharmacy: Physical–Chemical Principles
• Solubility
– A thermodynamic parameter impacts its usefulness as a
medicinal agent and also influences how a compound is
formulated, administered, and absorbed.
• Hydrophilicity/Lipophilicity
– The relative lipophilicity is important with respect to
biopharmaceutics since it affects partitioning into
biological membranes and therefore influences
permeability through membranes as well as binding and
distribution into tissues in vivo
• Salt Forms and Polymorphs
– The impact of pH and salt form on solubility, and how this
phenomenon can be utilized to manipulate the solubility
behavior of a drug compound
• Stability
– Important in order to avoid generation of undesirable impurities,
which could have pharmacologic activity and/or toxicologic
implications, in the drug substance or drug product
• Particle and Powder Properties
– Important from the perspective of a manufacturing process while
others could potentially impact drug product dissolution rate without
changing equilibrium solubility.
• Ionization and pKa
– Influences all of the physical–chemical properties discussed above.
The presence of an ionizable group leads to pH solubility effects,
which can be used to manipulate the physical properties and
biological behavior of a drug. For an ionizable compound, the aqueous
solubility of the ionized species is typically higher than the unionized
due to the greater polarity afforded by the presence of the ionized
functional group. The ionizable functional group and the magnitude of
the pKa determine whether a compound is ionized across the
physiological pH range, or if conversion between ionized/nonionized
species occurs in the GI tract, and if so, which region. The pKa also
affects the available choices of counterions for potential salt forms
that are suitable from a physical perspective.
 Formulation Principles
The goal is to manipulate the properties and environment
of the API to optimize its delivery to the target tissue by a
specific route of administration and to do so in a manner
compatible with large-scale product manufacture.
Excipients are added to solubilize, stabilize, modify
dissolution rate, improve ease of administration, enable
manufacturing, control release rate, or inhibit precipitation.
The formulation is key to a compound’s biopharmaceutical
profile since the composition, dosage form type,
manufacturing process, and delivery route are intimately
linked to pharmacokinetic results. A PK assessment cannot
be complete without inclusion of the relevant formulation
parameters to establish the appropriate context.
PHYSIOLOGICAL/BIOLOGICAL
PRINCIPLES
• Pharmacokinetics
– What the body does to the drug

• Pharmacodynamics
– What the drug does to the body
 PHARMACOKINETICS
• Pharmacokinetics involves
• Kinetics (temporal and spatial distribution of a substance in a system) of drug
absorption, distribution, and elimination (ie, excretion and metabolism)
• The study of pharmacokinetics involves
• Experimental - development of biological sampling techniques, analytical
methods for the measurement of drugs and metabolites, and procedures that
facilitate data collection and manipulation
• Theoretical approaches –development of pharmacokinetic models that
predict drug disposition after drug administration
• Statistical methods
• -used for pharmacokinetic parameter estimation and data interpretation
• -applied to pharmacokinetic models to determine data error and structural
model deviations. Mathematics and computer techniques form the
theoretical basis of many pharmacokinetic methods. Classical
pharmacokinetics is a study of theoretical models focusing mostly on model
development and parameterization.
 PHARMACOKINETICS (continued)
• Pharmacokinetics is the study of drug and/or
metabolite kinetics in the body. It deals with a
mathematical description of the rates of drug
movement into, within and exit from the body. It
also includes the study of drug metabolism or
biotransformation rates. The body is a very complex
system and a drug undergoes many steps as it is
being absorbed, distributed through the body,
metabolized or excreted (ADME).
Fate of Drug
 Pharmacokinetics

• What the body does to the drug

Drug at
Excretion
Absorption Excreted Drug
Site

Absorption
Drug in Body
Distribution

Metabolism
Metabolites

38
 Pharmacokinetic Terms

AUC Area Under the Curve or

Area under the concentration-time curve
Cmax Maximum (peak) drug concentration
Tmax Time of peak drug concentration
t1/2 Half-life; the amount of time required for the amount (or
concentration) of a drug to decrease by one-half
CL Systemic clearance; measure of the body’s ability to eliminate drug
(volume per unit time)
V Volume of distribution; relates the amount of drug in the body to
the concentration of drug in the blood

39
 Key Pharmacokinetic Parameters Illustrated

10

• Cmax: maximum observed

concentration
Cmax
Drug Concentration

• Tmax: time of Cmax

1
• Elimination half-life
t1/2 (t1/2 ): time to eliminate 50% of
the drug from the body

• AUC: area under the curve;

0.1 gauge of systemic
0 6 12 18 24 30 36 exposure/availability
Tmax Time (hrs)

40
 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. The
interaction of a drug molecule with a receptor causes
the initiation of a sequence of molecular events
resulting in a pharmacologic or toxic response.
Pharmacokinetic pharmacodynamic models are
constructed to relate plasma drug level to drug
concentration in the site of action and establish the
intensity and time course of the drug
 Pharmacodynamics

• What the drug does to the body

Drug at
Absorption Excreted Drug
Site Excretion

Drug in Body
Absorption

Distribution
Drug at
Metabolites
Effect Site Metabolism

Response
42
 Pharmacodynamic Terms

Emax Maximum effect

ED50 Dose which produces 50% (half) of the maximum effect
EC50 Concentration which produces 50% (half) of the
maximum effect

43
Key Pharmacodynamic Parameters Illustrated

80 Emax
70
• Emax: maximum observed
effect
60

50
• ED50: Dose which produces
PD Effect

40 50% (half) of the maximum

30 effect
20
ED50 or EC50
10 • EC50: Concentration which
0 produces 50% (half) of the
0 0.5 1 1.5 2
maximum effect
Dose or Concentration

44
 Plasma Level-Time Curve
• Generated by measuring the drug concentration
in plasma samples taken at various time intervals
after a drug product is administered
• The concentration of drug in each plasma sample
is plotted against the corresponding time at
which the plasma sample was removed.

• MEC – minimum effective concentration

• MTC – minimum toxic concentration
• Onset time
• Duration of drug action
• Peak plasma level
• Area Under the Curve, or AUC
Introduction to bipharmaceutics (Cont.):
 Introduction to bipharmaceutics (Cont.):
• Drug Product Performance Parameters:
1- Minimum effective concentration (MEC): The minimum
concentration of drug needed at the receptors to produce the
desired pharmacologic effect.

2- Minimum toxic concentration (MTC): The drug concentration

needed to just produce a toxic effect.

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

4- Duration of action: The difference between the onset time and

the time for the drug to decline back to the MEC.
 Introduction to bipharmaceutics (Cont.):
5- The time of peak plasma level: The time of maximum
drug concentration in the plasma and is proportional
to the rate of drug absorption.

6- The peak plasma level: The maximum drug

concentration, usually related to the dose and the rate
constants for absorption and elimination of the drug.

7- Area under the curve: It is related to the amount of

drug absorbed systemically.
 Biopharmaceutics
Drug in dosage form
Pharmacodynamics
Release

Drug particles in body fluids Pharmacologic effect

Dissolution

Degradation
Drug in solution Peripheral
Tissues
GI
Absorption Distribution

Liver Central Compartment

Excretion Free  Bound

Pharmacokinetics
50
 BASIC PHARMACOKINETICS
• Quantitative study of various kinetic processes
of drug disposition in the body.
• Drugs are in a dynamic State within the body.
• The biological nature of drug distribution and
disposition is complex
• Drug events often happen simultaneously.
 Basic pharmacokinetics requires –

• A thorough knowledge of anatomy and

physiology
• An understanding of the concepts and
limitations of mathematical models.
 PHARMACOKINETIC MODELS
• A model is a hypothesis using mathematical terms to
concisely describe quantitative relationships.
Simplifying assumptions are made to describe a
complex biologic system concerning the movement
of drugs. Various mathematical models can be
devised to simulate the rate processes of drug
absorption, distribution, and elimination. These
mathematical models make possible the
development of equations describe drug
concentrations in the body as a function of time.
 PHARMACOKINETIC MODELS (continued)

• The predictive capability of a model

• Proper selection and development of mathematical
function (s)
• Mathematical function (s) parameterizes the
essential factors governing the kinetic process.
• Key parameters in a process are commonly estimated
by fitting the model to the experimental data known
as variables.
• A pharmacokinetic function relates an independent
variable to a depend variable.
 Pharmacokinetic models are used to:
• Predict plasma, tissue, and urine drug levels.
• Calculate the optimum dosage regimen for each patient
individually.
• Estimate the possible accumulation of drugs and/or
metabolites.
• Correlate drug concentrations with pharmacologic or
toxicologic activity.
• Evaluate differences in the rate or extern of availability
between formulations (bioequivalence).
• Describe how changes in physiology or disease allect the
absorption, distribution, or elimination of the drug.
• Explain drug interactions.
 Compartment Models
• The body can be represented as a series, or systems, of
compartments that communicate reversibly with each other.
• A compartment is not a real physiologic or anatomic region
but is considered as a tissue or group of tissues that have
similar blood flow and drug affinity.
• Within each compartment, the drug is considered to be
uniformly distributed. Mixing of the drug within a
compartment is rapid and homogeneous and is considered to
be "well stirred,” so that the drug concentration represents an
average concentration, and each drug molecule lies an equal
probability of leaving the compartment.
 Compartment Models (continued)

• Compartment models are based on linear

assumptions using linear differential equations.
• Conceptually, drugs move dynamically in and out of
compartments.
• Rate constants are used to represent the overall rate
processes of drug entry into and exit from the
compartment.
• The model is an open system since drug can be
eliminated from the system.
 Mammillary Model
• Most common, consists of one or more peripheral
compartments connected to a central compartment.
• Central compartment assigned to represent plasma
and highly perfused tissues which rapidly equilibrate
-with drug.
• Elimination of drug occurs from the central
compartment since the organs involved in drug
elimination, primarily kidney and liver. are well-
perfused tissues.
 Mammillary Model (contd)
• Enables the pharmacokinelicist to write
differential equations to describe drug
concentration changes in each compartment
• Gives a visual repi oscillation of the lale
processes
• Shows how many pharmacokinetic constants
are necessary to describe llie process
adequately.
Various Mammilary Compartmental Model
 Catenary Model
In pharmacokinetics, the mammillary model must be distinguished from
another type of compartmental model called the Catenary model. The
catenary model consists of compartments joined to one another like the
compartments of a train. In contrast, the mammillarv model consists of one
or more compartments around a central compartment like satellites. Because
the catenary model does not apply to the way most functional organs in the
body are directly connected to the plasma, it is not used as often as the
mammillary model.
 Physiologic Pharmacokinetic Model
(Row Model)
• Blood flow or perfusion models – pharmacokinetic
models based on known anatomic and physiologic
data.
• Describe the data with the consideration that blood
flow is responsible for distributing drug to various
parts of the body.
• Uptake of drug into organs determined by the
binding of drug in these tissues.
• Actual tissue volume is used.
• Potentially predict realistic tissue drug
concentrations
 Row Model (contd)
– Drug concentrations are predicted by organ tissue size,
blood
– Blood flow, tissue size, and the drug tissue—blood ratios
may vary due to certain pathophysiologic conditions.
Thus, the effect of these variations on drug distribution
must be taken into account in physiologic
pharmacokinetic models.
– Physiologically based pharmacokinetic be applied to
several species, and, for some drugs, human data;
Extrapolation from animal data is not possible with the
compartment
Clinically, sound medical judgment
and observation are most
important. Therapeutic decisions
should not be based solely on
plasma drug concentrations.