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INTRODUCTION TO
BIOPHARMACEUTICS
AND
PHARMACOKINETICS

Course outcomes
By the end of the course you shall be able to:

▪ C803.1: Rewrite definitions of absorption, distribution,

metabolism, elimination, bioavailability, bioequivalence and
describe mechanisms of drug transport
▪ C803.2: Compile the various factors involved in absorption of
drugs
▪ C803.3: Summarize the processes and factors involved in
distribution, metabolism and eliminations of drugs
▪ C803.4: Describe pharmacokinetics and its mathematical
principles and apply the same to solve and interpret data from
simple pharmacokinetic models
▪ C803.5: Discriminate and recommend in vitro and in vivo
evaluation of dosage forms
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Syllabus

Unit Topic Hours Marks Test

no
1 Introduction 5 6 1
1.1 Introduction to the subject of biopharmaceutics and 2
Pharmacokinetics. Emphasis on the importance in drug
discovery, development and clinical pharmacy and
applications. Definitions: ADME, Bioavailability,
Bioequivalence
1.2 Drug Transport: Different mechanisms of drug 3
transport, physiology of cell membrane and passage of
drugs across cell membrane

Unit Topic Hours Marks Test

no
2 Absorption 10 12 2
2.1 Routes of drug administration: Emphasis on Oral, 2
parenteral and Extravascular routes (Self study)
2.2 Factors affecting drug absorption: Physicochemical 3
factors (Emphasis on pH partition theory and solubility)
2.3 Factors affecting drug absorption: Physiological factors 3
(Emphasis on physiology of GIT)
2.4 Factors affecting drug absorption: Formulation and 2
Dosage form factors (Self study)

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Unit Topic Hours Marks Test

no
3 Distribution 5 5 3
3.1 Factors affecting distribution: Physiological barriers, 2
Tissue permeability and perfusion limited distribution
3.2 Volume of Distribution – Concept, dependence on 1
site/fluid of measurement, limits of values of volume of
distribution
3.3 Protein Binding of drugs and its significance 2
Unit Topic Hours Marks Test
no
4 Metabolism 8 12 3
4.1 Phase I and Phase II reactions (self study) 3
4.2 Factors affecting drug metabolism: Age, species 2
difference, genetic difference, induction and inhibition,
drug- drug interaction
4.3 First pass metabolism, concept of clearance , hepatic 3
clearance and factors affecting hepatic clearance,
Hepatic extraction ratio, limits of values of organ
Clearance 5

Unit Topic Hours Marks Test no

5 Excretion 4 4 3
5.1 Renal excretion, Renal clearance and factors affecting 2
renal clearance, Excretion ratio
5.2 Non hepatic and non-renal routes of elimination 2
Unit Topic Hours Marks Test no
6 Dissolution 7 8 5
6.1 Introduction to Biopharmaceutical Classification 2
System of drugs
6.2 Theories of dissolution, Dissolution rate and methods of 3
enhancing dissolution rate.
6.3 Official and unofficial methods of dissolution rate 2
testing. Application to different dosage forms (self
study)
Unit Topic Hours Marks Test no
8 Bioavailability and bioequivalence 5 5 5
8.1 Concept of absolute and relative bioavailability 1
8.2 Methods of assessment and enhancement of 2
bioavailability (1 hour self study)
6
8.3 Bioequivalence: Study designs, Introduction to the 2
concept of biowaiver (1 hour self study)

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Unit Topic Hours Marks Test no

7 Pharmacokinetics 16 18 4
7.1 Pharmacokinetics: Introduction to compartmental and 3
physiological models. Introduction to the one
compartmental open model and its assumptions.
Concept of zero order and first order rate kinetics
7.2 Mathematical treatment of Pharmacokinetics upon 2
(One compartment open model) IV bolus dosing:
Importance of volume of distribution. Clearance,
elimination rate constant, half life, area under the curve
(trapezoidal rule)
7.3 Mathematical treatment of pharmacokinetics upon 3
(One compartment open model) extravascular dosing.
Absorption rate constant, absorption half life,
bioavailability. Area under the curve and the method of
residuals. Concept of Cmax and tmax.
7.4 Introduction to the rate of excretion method and Sigma 2
minus method for urine analysis after IV administration
7.5 Discussion of linear and nonlinear kinetics and 2
description of factors resulting in non linear kinetics
7.6 Application of PK principles through simple problems. 4
7
(3 hours self study)

Blue print
Que Unit Marks
Que Unit Marks no
Que Unit Marks
no 2 -- 11 no
1 -- 15 2a 2.1 3 5 -- 11
1a 1.1 2 2b 6.1/6.2 4 5a 1.2 4
1b 3.1 2 2c 7.6 4 5b 2.4 3
1c 3.2 1 3 -- 11 5c 8.2/8.3 4
1d 3.3 2 3a 2.2 3 6 -- 11
1e 4.1 1 3b 5.1/5.2 4 6a 4.1 4
1f 6.1 1 3c 7.3 4 6b 4.2 3
1g 6.2 1 4 -- 11 6c 7.4/7.5 4
1h 6.3 1 4a 2.3 3
Choice in questions 2,3,4 and 5 –
1i 7.2 2 4b 4.3 4
any 4 M question
1j 7.6 1 4c 7.1 3
8
1k 8.1 1 4d 6.3 1

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What happens when you take a

tablet?

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Biopharmaceutics ?

• Bioavailability (BA) describes the rate

and extent to which an active drug
Bioavailability ingredient or therapeutic moiety is
absorbed from a drug product and
becomes available at the site of action

• It is the study of factors influencing the

rate and amount of the drug that reaches
Biopharmaceutics the systemic circulation and the use of
this information to optimize the
therapeutic efficacy of drug products
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Pharmacokinetics

Definition

▪ Pharmacokinetics (PK): The kinetics of drug

absorption, distribution, metabolism and
elimination (KADME) and their relationship with the
pharmacological, therapeutic or toxicological
response in man and animals

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Absorption • The process of movement of drug from its site of

administration to systemic circulation

Distribution • The reversible movement of drug between one compartment

to other

• The process that tends to remove the drug from the body and
terminate its action

Elimination • Metabolism (biotransformation) – the process of inactivation

of drug by means of enzymes
• Excretion – the process of irreversible exit of drugs/
metabolites from the body
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LADME

Toxicology

Marketing Clinical

PK

Medicinal
Pharmaceutics
chemistry

Regulatory

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How is a drug developed?

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Pharmaceutical
phase

Pharmacokinetic
phase

Pharmacodynamic
phase

Therapeutic phase

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The Impact of Pharmacokinetics

▪ On an average every
new drug molecule
requires 12–15 years to
reach the patient and
costs a staggering
amount of US $2.6
billion

1,75,53,17,20,000 Indian Rupees

Rupees One Seventy Five Fifty Three

Crore Seventeen Lakh Twenty
Thousand only

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Reasons for attrition of drugs between 1990 and

2000

It was a major contributor for attrition of

drugs in 1990s

▪ From 1964 to 1985, approximately 39% of drug

candidates failed clinical development due to their PK
characteristics
▪ Although by 2000 this had been reduced to 8%
▪ Dramatic improvement in 2000
▪ This was accomplished by a deliberate policy of 'front
loading' PK considerations into the drug discovery
process by introducing a variety of screens, many being
in vitro assays, designed to help select compounds with
desirable PK properties

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Case study 1 - Discovery of

Fluconazole

▪ Pfizer’s tioconazole was clinically effective against

fungal infections of the vagina and skin but failed
to act systemically when given intravenously or
orally
▪ BP and PK studies revealed that drug was
reasonably well absorbed but underwent extensive
first pass metabolism and high protein binding

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▪ Efforts to decrease lipophilicity of the molecule

lead to the novel systemic antifungal agent, i.e.
fluconazole

Case study 2: Discovery of Indinavir

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Molecule Modification Observation

L-364,505 First Merck compound that was
identified to be a potent HIV protease
inhibitor in vitro, with an CIC95 . 100
mcgM). It had strong renin activity
L-687,908 Increase in anti-viral activity and
eliminate renin activity
L-689,502 Improve the solubility by adding polar
groups to the compounds without
compromising their antiviral activity.
Indinavir Addition of a pyridine.
This compound was not active
Showed a good activity in the
viral spread assay with a CIC of
12 nM. The compound was not
orally available in animals, and
was too insoluble
CIC95 of 12 nM.
5% orally bioavailable in dogs
Bioavailability more than 65%.
Approved by FDA in April 1996
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Case study 3: discovery of enalapril

The most common side effects accompanying the clinical use of

captopril are rashes and taste dysfunction

Similar side effects are observed with penicillamine, which is a

sulfhydryl-containing heavy metal antagonist

It is therefore speculated that captopril interacts with

endogenous sulfhydryl-containing proteins to form disulfides

These disulfides act as haptens, resulting in immunological

reactivity, which may be responsible for these side effects

Enalaprilat and lisinopril were designed to avoid these

undesirable side effects by removal of the sulfhydryl group
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Enalaprilat has low partition

coefficient (Approx 0.003)

Thus it is poorly absorbed (less

than 10%)

Enalaprilat was developed as its

ethyl ester prodrug (enalapril) to
increase its bioavailability

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Case study 4: Discovery of

paracetamol

Converted to at least 1 Eg. N-

Phenacetin
dozen metabolites hydroxyphenatidine

responsible for the

It is an O-deethylated formation of
Thus paracetamol was
metabolite of methemoglobin and
developed
phenacetin hemolysis of red blood
cells
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Case study 5: Discovery of

amlodipine
Nifedipine Short half life (~ 2 hrs) t.i.d. dosage regimen

Addition of an alkyl
Also undergoes
amine side-chain linked Exhibits large
substantial first pass
to the dihydropyridine interpatient variability
metabolism
2-methyl group

Amlodipine (half life ~

30 hrs)

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Pharmacodynamic and
Pharmacokinetic
Parameters

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Plasma level – time studies

▪ 2 categories of factors that can be evaluated from

plasma concentration time profile:

▪ PK parameters

▪ PD parameters

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PK parameters
Peak plasma conc. • The point of maximum conc of drug in plasma is peak and the conc at peak is
known as peak plasma conc
(Cmax)
Time for peak conc. • Time for drug to reach peak plasma conc after ev administration
(tmax)
Area under the curve • It is the total integrated area under the plasma level-time profile and expresses
the total amount of drug that comes into systemic circulation after its
(AUC) administration

Elimination half life • Time required for drug conc to fall to half of its original value
(t1/2)
• Hypothetical volume of blood fluids containing drug from which the drug is
Clearance (Cl) removed or cleared completely in a specific period of time

Volume of distribution • The hypothetical volume of body fluid into which a drug is dissolved or
distributed
(Vd)

Pharmacokinetic parameters of
paracetamol and chloroquine

Oral bioavailability (F) 70%-90% ~ 90%

Rectal bioavailability 30%-70% ~ 25%
Clearance (CL) 20 L/h 282 to 1139 ml/min
15000L (Highly lipophilic
Volume of distribution
65 L molecules which sequester
(Vd)
into total body fat.)
Half-life (t1/2) 2–4 h 1 – 2 months
Plasma protein binding < 20 % 55 %
Conjugation with glucuronic
In liver to
Metabolism acid (55%) and sulfuric acid
desethylchloroquine
(35%)
Only 2-5% of the dose is
Excretion excreted in an unchanged ≥50% as unchanged drug
form in the urine 38

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PD parameters
Minimum effective conc (MEC) • Minimum conc of drug in plasma required to produce a therapeutic effect

Maximum safe conc. (MSC)/ • Conc of drug in plasma above which adverse or unwanted effects are
(MTC) precipitated

Onset of action • The beginning of pharmacological response

• The time required for the drug to start producing pharmacological

Onset time response

• Time period for which the plasma conc of drug remains above the MEC
Duration of action level

• It is the maximum pharmacological response produced by the peak

Intensity of action plasma conc of drug

Therapeutic range • The plasma drug conc range between MEC and MTC

Therapeutic index • The ratio of MTC to MEC

Bioavailability and bioequivalence

Bioavailability

Types

Absolute Relative

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Bioavailability is defined as the rate and extent to which is

a drug substance gets absorbed and becomes available at
the site of action

Absolute bioavailability Relative bioavailability

▪ It is the comparison of ▪ It is the comparison of

bioavailability of a drug bioavailability of a secondary
given by ev route as product with the innovator’s
opposed to that given by product.
an iv route 𝐴𝑈𝐶𝑡𝑒𝑠𝑡 𝐷𝑜𝑠𝑒𝑟𝑒𝑓
𝐴𝑈𝐶𝑒𝑣 𝐷𝑜𝑠𝑒𝑖𝑣
▪ 𝐹= 𝐴𝑈𝐶𝑟𝑒𝑓
𝑋 𝐷𝑜𝑠𝑒𝑡𝑒𝑠𝑡
X 100
▪ 𝐹= 𝐴𝑈𝐶𝑖𝑣
𝑋 𝐷𝑜𝑠𝑒𝑖𝑣
X 100

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Bioequivalence
▪ The absence of a significant difference in the rate and extent to
which the active ingredient in pharmaceutical equivalents or
pharmaceutical alternatives becomes available at the site of drug
action when administered at the same molar dose under similar
conditions in an appropriately designed study.

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Pharmaceutical • They contain the same amount of the same

active substance in the same dosage form that
equivalents meet the same or comparable standard.

• They contain the same active moiety but differ

in:
Pharmaceutical • Chemical form of that moiety, or
alternatives • In the dosage form, or
• Strength.

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So let’s test your basics

now

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1. Which does the term

pharmacokinetics not include?

a) Clinical response to a drug ie; toxicity & efficacy

b) Drug concentration at site of action
c) Dose of drug administered
d) Drug metabolized or excreted

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2.Most drugs enter the venous side of

circulation; which route is the exception?

A. IV injection
B. IM injection
C. Suppository
D. Inhalation

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3. A drug that might cause an upset stomach if

taken orally can alternatively be administered via
which route?

A. Injection into the gut

B. Sublingual route
C. Topical patch
D. Rectal suppository

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4.Little Billy has accidentally ingested a toxic chemical which has

made him unconscious and will soon kill him. Which route of
administration will ER physicians most likely use to administer an
antidote for this toxin?

A. IV
B. Oral
C. Topical
D. Rectal

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5. The primary route of excretion

route for drugs from the body is?

A. Liver
B. Kidneys
C. Lungs
D. Intestines

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6. The primary organ that

metabolizes drugs in the body is?

A. Liver
B. Lungs
C. Kidneys
D. Intestines

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7. Which route allows cocaine to get

into the brain fastest (another one is a
very close second)?

A. IV injection
B. Inhalation
C. Oral
D. Rectal

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8. Which route(s) of administration

completely bypass the first pass effect?

A. Transdermal & sublingual

B. Rectal and oral
C. Rectal, transdermal & sublingual
D. Oral

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9. When morphine is administered

orally, only 40-50% reaches the CNS...
why does this happen?

a) Drugs administered orally are exposed to the liver and

may be extensively metabolized before reaching the rest
of the body (first pass effect)
b) Drugs administered orally enter directly into systemic
circulation and because of highly fenestrated endothelial
capillary cells make it to the brain quickly
c) Why are you giving it orally? Give it rectally
d) Less contact time at the absorption site

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10. Which of the following is NOT a

parenteral route of administration?

A. IV
B. IM
C. Subcutaneous
D. Sublingual

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1. Which does the term

pharmacokinetics not include?

a) Clinical response to a drug ie; toxicity & efficacy

b) Drug concentration at site of action
c) Dose of drug administered
d) Drug metabolized or excreted

55

2.Most drugs enter the venous side of

circulation; which route is the exception?

A. IV injection
B. IM injection
C. Suppository
D. Inhalation

56

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3. A drug that might cause an upset stomach if

taken orally can alternatively be administered via
which route?

A. Injection into the gut

B. Sublingual route
C. Topical patch
D. Rectal suppository

57

4.Little Billy has accidentally ingested a toxic chemical which has

made him unconscious and will soon kill him. Which route of
administration will ER physicians most likely use to administer an
antidote for this toxin?

A. IV
B. Oral
C. Topical
D. Rectal

58

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5. The primary route of excretion

route for drugs from the body is?

A. Liver
B. Kidneys
C. Lungs
D. Intestines

59

6. The primary organ that

metabolizes drugs in the body is?

A. Liver
B. Lungs
C. Kidneys
D. Intestines

60

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7. Which route allows cocaine to get

into the brain fastest (another one is a
very close second)?

A. IV injection
B. Inhalation
C. Oral
D. Rectal

61

8. Which route(s) of administration

completely bypass the first pass effect?

A. Transdermal & sublingual

B. Rectal and oral
C. Rectal, transdermal & sublingual
D. Oral

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9. When morphine is administered

orally, only 40-50% reaches the CNS...
why does this happen?

a) Drugs administered orally are exposed to the liver and

may be extensively metabolized before reaching the rest
of the body (first pass effect)
b) Drugs administered orally enter directly into systemic
circulation and because of highly fenestrated endothelial
capillary cells make it to the brain quickly
c) Why are you giving it orally? Give it rectally
d) Less contact time at the absorption site

63

10. Which of the following is NOT a

parenteral route of administration?

A. IV
B. IM
C. Subcutaneous
D. Sublingual

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