Transcript The Biopharmaceutical Classification System (BCS)

The Biopharmaceutical
Classification
System (BCS)
Dr Mohammad Issa
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Biopharmaceutical Classification
System (BCS)
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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:
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Solubility
Permeability
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Biopharmaceutical Classification
System (BCS)
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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
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BCS Classes
Class I
Highly permeable
Highly soluble
Class II
Highly permeable
Poorly soluble
Class III
Poorly permeable
Highly soluble
Class IV
Poorly permeable
Poorly soluble
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Biopharmaceutical Classification
System (BCS)
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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%
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Biopharmaceutical Classification
System (BCS) objectives
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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
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BCS Class I: High Solubility and
High Permeability
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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
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BCS Class I: High Solubility and
High Permeability
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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.
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BCS Class II: Poor Solubility and
High Permeability
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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-tosolubility 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
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BCS Class II: Poor Solubility and
High Permeability
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Formulations designed to overcome
solubility or dissolution rate
problems:
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Salt formation
Particle size reduction
Metastable forms
Solid dispersion
Complexation
Lipid based formulations
Precipitation inhibitors
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BCS Class III: High Solubility and
Low Permeability
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Since passive diffusion is the ratelimiting 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:
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Prodrugs
Permeation enhancers
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BCS Class IV: Low Solubility and
Low Permeability
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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
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Case Study I: Use of the BCS in
Formulation Development
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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)
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Case Study I: Use of the BCS in
Formulation Development
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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
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Case Study I: Use of the BCS in
Formulation Development
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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
Case Study I: Use of the BCS in
Formulation Development
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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
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Modifications to BCS classification
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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)
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Biopharmaceutical Drug Disposition
Classification System (BDDCS)
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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
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Biopharmaceutical Drug Disposition
Classification System (BDDCS)
BDDCS class I
High solubility
Extensive
metabolism (Rapid
dissolution and 70%
metabolism for
biowaiver)
BDDCS class III
High solubility
Poor metabolism
BDDCS class II
Low solubility
Extensive
metabolism
BDDCS class IV
Low solubility
Poor metabolism
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BDDCS advantages
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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
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BDDCS for predicting transporter
effect on oral absorption
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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.
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BDDCS for predicting transporter
effect on oral absorption
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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.
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BDDCS for predicting transporter
effect on oral absorption
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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.
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