The Biopharmaceutical Classification System (BCS) : DR Mohammad Issa

The Biopharmaceutical
Classification
System (BCS)
Dr Mohammad Issa
1
Biopharmaceutical Classification
System (BCS)
 Biopharmaceutics Classification System

(BCS) is a predictive approach to relate
certain physicochemical characteristics
of a drug substance and drug product
to in-vivo bioavailability
 BCS categorized drugs according to two

key physico-chemical parameters:
 Solubility
 Permeability
2
System (BCS)
 These two factors were selected because

most orally administered drugs are
absorbed via a passive diffusion process
through the small intestine, where the
extent of oral absorption is largely
influenced by a drug’s membrane
permeability and solubility
3
BCS Classes
Class I Class II
Highly permeable Highly permeable
Highly soluble Poorly soluble
Class III Class IV

Poorly permeable Poorly permeable
Highly soluble Poorly soluble
4
System (BCS)
 According to the FDA guidelines, a high

solubility drug is defined as one that, in the
largest dose strength, fully dissolves in 250
mL of aqueous medium with the pH ranging
from 1 to 7.5 at 37 ° C. Otherwise, drugs
are considered poorly soluble. In other
words, the highest therapeutic dose must
dissolve in 250 mL of water at any
physiological pH
 In the same guidance as mentioned above,

a drug is considered highly permeable if the
extent of oral absorption is greater than
90% 5
System (BCS) objectives
 to guide decisions with respect to in

vivo and in vitro correlations and the
need for bioequivalence studies
 to provide a useful framework to

identify appropriate dosage form
designs that are aimed at overcoming
absorption barriers posed by solubility
and permeability related challenges
6
BCS Class I: High Solubility and
High Permeability
 Compounds belonging to this class are

normally expected to dissolve quickly in
gastric and intestinal fluids, and readily cross
the intestinal wall through passive diffusion
 BCS Class I are unlikely to show

bioavailability or bioequivalence issues
 Therefore, for BCS class I drugs, in vitro

dissolution studies are thought to provide
sufficient information to assure in vivo
product performance making full in vivo
bioavailability / bioequivalence studies
unnecessary 7
BCS Class I: High Solubility and
High Permeability
 Although class I compounds are expected to

have excellent oral absorption, given their
high solubility and high permeability,
additional absorption barriers may exist
beyond the scope of the BCS
 For example, luminal complexation and

degradation can significantly limit the amount
of drug available for absorption. Even after
the drug crosses the intestinal membrane, it
may be metabolized within the
enterocytes/hepatocytes and/or pumped out
of the cells due to efflux mechanisms.
8
BCS Class II: Poor Solubility and
High Permeability
 By definition, poor solubility and/or slow
dissolution are the rate-limiting steps for oral
absorption of BCS class II compounds
 For compounds with a very large dose-to-

solubility ratio, poor solubility is likely to be the
rate-limiting step for absorption.
 In other words, the compounds may dissolve

quickly enough to reach their equilibrium
solubility, but the solubility is too low to establish
a wide enough concentration gradient to drive
passive diffusion
9
BCS Class II: Poor Solubility and
High Permeability
 Formulations designed to overcome

solubility or dissolution rate
problems:
 Salt formation
 Particle size reduction
 Metastable forms
 Solid dispersion
 Complexation
 Lipid based formulations
 Precipitation inhibitors
10
BCS Class III: High Solubility and
Low Permeability
 Since passive diffusion is the rate-

limiting step for oral absorption of BCS
class III compounds, the most
effective way to improve absorption
and bioavailability of this class of
compounds is to increase the
membrane permeability
 Approaches to improve permeability:

 Prodrugs
 Permeation enhancers
11
BCS Class IV: Low Solubility and
Low Permeability
 Class IV compounds exhibit both poor

solubility and poor permeability, and they
pose tremendous challenges to
formulation development
 As a result, a substantial investment in

dosage form development with no
guarantee of success should be expected
 A combination of class II and class III

technologies could be used to formulate
class IV compounds, although the success
rate is not expected to be high 12
Case Study I: Use of the BCS in
Formulation Development
 Pregabalin (Lyrica®) is is indicated for the

management of neuropathic pain
associated with diabetic peripheral
neuropathy, management of postherpetic
neuralgia, adjunctive therapy for adult
patients with partial onset seizures, and
management of fibromyalgia
 Pregabalin is a BCS Class 1 compound

(highly permeable and highly soluble).
Pregabalin is an amino acid and its lowest
aqueous solubility occurs at its isoelectric
point (at pH 7.4)
13
 It is considered high solubility as the
amount of water needed (<10 mL) to
dissolve the highest dose strength (300
mg) at pH 7.4 is less than the 250 mL
criteria. Pregabalin meets the BCS criteria
for a highly permeable compound as
greater than 90% of the dose is excreted
unchanged in the urine
 Three different series of formulations

were used during clinical development.
Each series was comprised of one to three
different dose strengths. Strengths within
each series were content proportional
with respect to drug and excipients 14
 All three series used the same excipients;
however the relative proportion of each
excipient was different for each series
 Bioequivalence between and among these

formulations and the commercial
formulation was established for this BCS
Class 1 compound by demonstrating that
all formulations were rapidly dissolving
and had similar dissolution profiles over a
pH range of 1.2 to 6.8
 Thus bioequivalence was demonstrated

using dissolution data and waivers of in
vivo bioequivalence studies were granted15
 Application of BCS had significant impact on
the cost of clinical development program for
pregabalin.
 It has been estimated that this example

saved the company more than $1,000,000
compared to a more traditional approach that
would have utilized four separate
bioequivalence studies
 Further, indirect savings are equally

impressive. Considering that yearly
Pregabalin sales exceed $1,200,000,000,
each month of times saving equates to an
additional $100,000,000 in sales prior to loss
of patent exclusivity 16
Modifications to BCS classification
 A major limitation of the BCS is that it
does not provide an in-depth
understanding of how drug metabolism
and drug transport may impact the
pharmacokinetic performance of drug
products
 In 2005, Wu and Benet proposed a

modified version of classification system—
the biopharmaceutical drug disposition
classification system (BDDCS)
17
Biopharmaceutical Drug Disposition
Classification System (BDDCS)
 After reviewing 130 drugs listed in the WHO
Essential Medicines List in terms of their
solubility, permeability, and pharmacokinetic
parameters, they found a common theme
linked the BCS to drug metabolism.
 The high permeability of BCS class I and II

compounds allows ready access to the
metabolizing enzymes within hepatocytes.
Therefore, compounds in classes I and II are
eliminated primarily via metabolism
 Compounds in classes III and IV have low

permeability, and are primarily eliminated
unchanged into the urine and bile
18
Biopharmaceutical Drug Disposition
Classification System (BDDCS)
BDDCS class I BDDCS class II

High solubility Low solubility
Extensive Extensive
metabolism (Rapid metabolism
dissolution and 70%
metabolism for
biowaiver)
BDDCS class III BDDCS class IV
High solubility Low solubility
Poor metabolism Poor metabolism
19
BDDCS advantages
 May provide a useful framework to predict
effects of food, enzyme transporter
interplay, and drug–drug interactions on
the pharmacokinetic performance of drug
products
 it is easier to obtain accurate metabolism
data than permeability data
 BDDCS could provide a useful framework
to predict drug disposition profiles, as well
as to expand the number of class I
compounds eligible for waiver of in vivo
bioequivalence study
20
BDDCS for predicting transporter
effect on oral absorption
 High solubility and high
permeability of class I compounds
allows a high concentration in the
gut to saturate both the
absorptive and efflux transporter.
 As a result, transporters will not

play a significant role affecting
oral absorption of class I
compounds.
21
 The high permeability of class II
compounds allows their ready
access across the gut membrane,
and implies that absorptive
transporters will not have an
effect on absorption. But their low
solubility prevents saturation of
the efflux transporter, resulting in
the dominant effect of efflux
transporters on oral absorption of
this class of compounds.
22
 The low permeability/high
solubility of class III compounds
indicates that an absorptive
transporter will affect the extent
of oral bioavailability and rate of
absorption of the class III
compounds.
 Both the absorptive and efflux

transporters could have a
significant effect on oral
absorption of class IV
compounds. 23
24

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The Biopharmaceutical

 Biopharmaceutics Classification System

 BCS categorized drugs according to two

 These two factors were selected because

Class III Class IV

 According to the FDA guidelines, a high

 In the same guidance as mentioned above,

 to guide decisions with respect to in

 to provide a useful framework to

 Compounds belonging to this class are

 BCS Class I are unlikely to show

 Therefore, for BCS class I drugs, in vitro

 Although class I compounds are expected to

 For example, luminal complexation and

 For compounds with a very large dose-to-

 In other words, the compounds may dissolve

 Formulations designed to overcome

 Since passive diffusion is the rate-

 Approaches to improve permeability:

 Class IV compounds exhibit both poor

 As a result, a substantial investment in

 A combination of class II and class III

 Pregabalin (Lyrica®) is is indicated for the

 Pregabalin is a BCS Class 1 compound

 Three different series of formulations

 Bioequivalence between and among these

 Thus bioequivalence was demonstrated

 It has been estimated that this example

 Further, indirect savings are equally

 In 2005, Wu and Benet proposed a

 The high permeability of BCS class I and II

 Compounds in classes III and IV have low

BDDCS class I BDDCS class II

Poor metabolism Poor metabolism

 As a result, transporters will not

 Both the absorptive and efflux

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