Introduction to Biopharmaceutics

and Pharmacokinetics

Dr. Khondker Ayesha Akter

Assistant Professor
Department of Pharmaceutical Sciences
North South University
 Biopharmaceutics
Definition: Biopharmaceutics is the area of pharmaceutical
science that examines the interrelationship of the
physicochemical properties of the drug, the dosage form and
the route of administration on the rate and extent of systemic
drug absorption.
Biopharmaceutics involves factors that influence:
the stability of the drug within the drug product
the release of the drug from the drug product
the rate of dissolution/release of the drug at the
absorption site, and
the systemic absorption of the drug
 Biopharmaceutics
Studies in biopharmaceutics use both in-vitro and in-vivo
methods.
In-vitro methods are procedures employing test apparatus
and equipment without involving laboratory animals or
humans. But if cells are separated from animal/plant and used
for investigation of drug effect is also included in in vitro.
In-vivo methods are more complex studies involving human
subjects or laboratory animals.
These methods must be able to assess the impact of the
physical and chemical properties of the drug, drug stability,
and large-scale production of the drug and drug product on
the biologic performance of the drug.
 Pharmacokinetics
Pharmacokinetics is the branch of science which deals with
drug absorption, distribution, metabolism and excretion. In
simple word pharmacokinetics deals with what body does to
the drug.
• Distribution + metabolism + excretion = disposition
• Metabolism + excretion = elimination
 After a drug is released from its dosage form, the drug is
absorbed and distributed into the surrounding tissue
through the blood circulation.
 Then the drug molecules are broken down to metabolites
and finally excreted from the body by different routes.
 Some drugs are not metabolized and hence extracted as
intact molecule via different excretion routes.
A general scheme describing the relationship
among different processes:

Drug in the
Disintegration Dissolution
dosage form
Absorption

Drug in the
Drug in the Cell
Systemic
and Tissue Distribution Circulation

Elimination
Pharmacologic
Metabolism &
Effect Excretion
 Biopharmaceutics vs Pharmacokinetics

 Biopharmaceutics takes the interaction of API and

excipients of the dosage form into consideration; but
pharmacokinetics deals with ADME of pure drug molecule.
 Release of drug from the dosage form is discussed in
biopharmaceutics but not in pharmacokinetics.
 Biopharmaceutics is related to pharmaceutics on the other
hand pharmacokinetics is more related to pharmacology.
 Biopharmaceutics deals with how properties of drug and
dosage form affects the administration process and
absorption.
 Pharmacokinetics deals with how the properties of only
drug affects ADME.
 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.
 It deal with what drug does to the body.
 Mechanism of action and dose-response relationship.
 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.
 Though drugs are administered for their therapeutic
effects, side effects and inevitable.
 Differences between pharmacokinetics and
pharmacodynamics
Pharmacokinetics Pharmacodynamics
What body does to the drug What drug does to the body
It encompasses- It includes-
•Absorption •Mechanism of action
•Distribution •Interaction with receptor
•Elimination •Therapeutic effect, side effects
It deals with plasma level of It deals with dose-response
drug with time relationship
 Pharmacokinetic & Pharmacodynamic models
 A model is a hypothesis using mathematical terms to
describe quantitative relationships concisely.
 Pharmacokinetic-pharmacodynamic models are constructed
to relate plasma drug level to drug concentration at the site
of action and establish the intensity and duration of action of
the drug.
 Drugs are in a dynamic state within the body as they move
between tissues and fluids, bind with plasma or cellular
components, or are metabolized.
 The inherent and infinite complexity of these events require
the use of mathematical models and statistics to estimate
drug dosing and to predict the time course of drug efficacy
for a given dose.
Use of pharmacokinetic-Pharmacodynamic models
• Predict plasma, tissue, and urine drug levels with any
dosage regimen
• 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 extent of availability
between formulations (bioequivalence)
• Describe how changes in physiology or disease affect the
absorption, distribution, or elimination of the drug
• Explain drug interactions
 Mammillary and Catenary Models
The mammillary model is the most common compartment
model used in pharmacokinetics. In the 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
equilibrate with drug. 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, primarily
kidney and liver, are well-perfused tissues.
The catenary model consists of compartments joined to one
another like the compartments of a train. In contrast, the
mammillary model consists of one or more compartments
around a central compartment like satellites.
 Mammillary and Catenary Models
Compartment-2

kc2 k2c

kc1 Central kc3

Compartment-1 Compartment-3
Compartment
k1c kc3

k4c kc4

Compartment-4

k12 k23
Compartment-1 Compartment-2 Compartment-3
k21 k32
 Biopharmaceutical Classification System (BCS)

Definition: The Biopharmaceutical Classification System (BCS)

is a model to categorize the drugs on the basis of their solubility
and permeability.
It is based on the solubility and permeability of highest
dose strength of API from an immediate release product
after oral administration.
The solubility classification is based on a United States
Pharmacopoeia (USP) aperture.
Since the majority of drugs are orally dosed, the system
was designed around oral drug delivery.
The intestinal permeability classification is based on a
comparison of oral dosage form to the IV injection.
 Purpose of the BCS Guidance
 The main purpose of the system is to aid in the regulation of post-
approval changes and generics, providing approvals based solely
on in vitro data when appropriate.
 To improve the efficiency of drug development and the review
process by recommending a strategy for identifying expendable
clinical bioequivalence tests.
 To recommend a class of immediate-release (IR) solid oral dosage
forms for which bioequivalence study is necessary based on in
vitro dissolution tests.
 To recommend methods for classification according to dosage form
dissolution, along with the solubility and permeability
characteristics of the drug substance.
 Explains when a waiver for in vivo bioavailability and
bioequivalence studies may be requested.
 Class boundaries for BCS
 A drug substance (API) is considered highly soluble when the
highest dose strength is soluble in less than 250 ml water over
a pH range of 1.0-7.5.
 A drug substance is considered highly permeable when the
extent of absorption in humans is determined to be more than
90% of an administered dose, in comparison to an intravenous
(IV) reference dose.
 A drug product (dosage form) is considered to be rapidly
dissolving when more than 85% of the labeled amount of API
dissolves within 30 minutes using USP apparatus I or II in a
volume of <900 ml buffer solutions.
 All those factors are highly important because 85% of the most
sold drugs in the United States and Europe are orally
administered.
 Four classes of drug according to BCS
According to the Biopharmaceutics Classification System
(BCS) drugs are classified into four classes upon their
solubility and permeability:
A. Class-I (High permeability, high solubility)
B. Class-II (High permeability, low solubility)
C. Class-III (Low permeability, high solubility)
D. Class-IV (Low permeability, low solubility)

 Permeability can be determined by a number of ways but is

most often done using Caco-2 cell lines.
 In this system a monolayer of cells is grown and drug
permeation from the drug donor (apical side) to the
acceptor (basolateral side) compartments is assessed,
usually by direct UV or LC-MS assay. 
Biopharmaceutical Classification System (BCS)
 Class I: High permeability, high solubility
 By definition, BCS Class I drugs are highly absorbed, and
have neither solubility nor permeability limited absorption.
 Therefore they generally represent a low risk group of
compounds in terms of the potential for excipients to affect
absorption, compared to other BCS classes.
 Example: Metoprolol, paracetamol, propranolol, verapamil.
 For those drugs formulation considerations of oral dosage
form is the simplest.
 Sustained release or extended release solid dosage forms
can be prepared easily.
 In industrial practice, the stability consideration of dosage
form is evaluated carefully in this case.
 Class II: High permeability, low solubility
 The bioavailability of those drugs are limited by their
solvation rate.
 Dissolution is the rate limiting step in the process of
bioavailability in these type of drugs.
 A BCS Class II drug would not be a good clinical candidate
without the use of enhanced formulation techniques aimed
at increasing solubility or rate of dissolution.
 A correlation between the in vivo bioavailability and the in
vitro solvation can be found.
 These drugs are not usually considered for the preparation
of sustained release dosage forms.
 Example: glibenclamide, phenytoin, aceclofenac,
ketoprofen, naproxen, carbamazepine.
 Class III - low permeability, high solubility

 The absorption is limited by the permeation rate but the drug

is solvated very fast.
 If the formulation does not change the permeability or
gastro-intestinal transit time, then class I criteria can be
applied for those drugs.
 Example: cimetidine, ranitidine, vancomycin, atenolol.
 Most pharmaceutical proteins and peptides are considered
to be BCS Class III drugs, thus having a good solubility but
poor permeability, which leads to an overall poor
bioavailability.
 Furthermore, poor stability and short plasma half-life are
major drawbacks.
Eligibility of a C-3 drug product for a BCS-based biowaiver

Are there excipients in the

formulation with known or suspected
effects on drug absorption?

Yes

No Are there excipients which may

Yes affect absorption within ±10% of
the amount of the excipients in
the reference product?

Are all excipients

No No
qualitatively and
quantitatively similar?

Yes

Biowaiver possible, if dissolution Biowaiver will not be granted

similarity is demonstrated between unless appropriate justification
the test and reference formulations can be provided
 Class IV: Low permeability, low solubility

 Those compounds have a poor bioavailability after oral

administration.
 If given by IV or IA route they will have very poor volume of
distribution.
 Usually they are not well absorbed over the intestinal
mucosa and a high variability in plasma concentration and
response is observed.
 Example: Bifonazole, furosemide, hydrochlorothiazide.
 Those drugs may be considered for further study to optimize
solubility and permeability as well as SAR.
 Use of BCS in dosage form design
 In early drug development, BCS helps guide the selection of
drug candidates through quantitative and predictive models; it
enables pharmaceutical companies to streamline formulation
strategies and discover better compounds.
 Most pharmaceutical companies have integrated
consideration of profiling data, including solubility and
permeability.
 Upon consideration of BCS parameters, if a new compound
is categorized as Class II, III, or IV, it indicates to discover the
need to improve solubility and/or permeability for the drug
molecule.
 It indicates to Manufacturing that there may be greater
formulation risks during development; and it indicates to
clinicians that there is a potential for large variability in
exposure and a significant food effect.
How is BCS used by Pharmaceutical Industry?

BCS Permeability Solubilit Oral dosage form consideration

Class y
Class I High High Simple, solid oral dosage form
Class II High Low Solution is the best
Suspension better
Techniques necessary to increase
surface area
Tablet, capsule need incorporation of
solubilizer
Class Low High Incorporation of permeability
III enhancer is necessary, maximization
of local luminal concentration
Class Low Low Not suitable for oral dosage form
IV Combination of 2 and 3
 How is BCS used by regulatory authority?
The FDA pioneered efforts to establish BCS as a regulatory
tool in the drug approval process. In 2000, the US Food and
Drug Administration (FDA) published a guideline that allowed
sponsors to justify requests to waive in vivo bioequivalence
study requirements for immediate release solid oral dosage
forms based on BCS criteria, so-called biowaivers.
According to FDA, demonstration of bioequivalence may not
be necessary for substances that are highly soluble and
highly permeable (i.e., fall into Class I) and exhibit rapid
dissolution.
This classification system helps to establish in vitro in vivo
correlation (IVIVC).
Permeability based classification of drugs
High Permeability Moderate Permeability Low Permeability
(fa ≥85%) (fa 50-85%) (fa <50%)
Antipyrine Chlorpheniramine Famotidine
Caffeine Creatinine Nadolol
Ketoprofen Terbutaline Sulpiride
Naproxen Hydrochlorothiazide Lisinopril
Theophylline Enalapril Acyclovir
Metoprolol Furosemide Foscarnet
Propranolol Metformin Mannitol
Carbamazepine Amiloride Chlorothiazide
Phenytoin Atenolol
Disopyramide Ranitidine
Minoxidil

Zero Permeability
FITC-Dextran, Polyethylene glycol 4000,
Lucifer yellow, Inulin, Lactulose
Biopharmaceutic consideration in dosage
from design
Parameter Considerations
Therapeutic Drug may be intended for rapid relief of symptoms, or longer
objectives for chronic use; some drug may be intended for local action or
systemic action
Properties of API Physical and chemical properties of API, including solubility,
polymorphic form, particle size; impurities
Route of Oral, topical, parenteral, transdermal, inhalation, etc
administration
Dose and dosage Large or small drug dose, frequency of doses, patient
regimen acceptance of drug product, patient compliance
Type of dosage Orally disintegrating tablets, immediate release tablets,
form extended release tablets, transdermal, topical etc.
Excipients Excipients may affect drug product performance by altering
release of drug from drug product
Manufacturing Variables in manufacturing processes, including weighing
process accuracy, blending uniformity, release tests, and product
sterility for parenterals