Advances in Technology & Business

Potential of New Drug Delivery

Systems including Recent Advances in
Biopharmaceutics: BCS and BDDCS
Leslie Z. Benet, Ph.D.
Department of Biopharmaceutical Sciences
University of California, San Francisco

8th International Symposium of CRS

Indian Chapter
Ahmedabad

February 26, 2008

Rationale for NDDS

a Commercial only (no delivery advantages)
a Extended or delayed release to allow more
convenient dosing interval
a Increase drug solubility
a Increase drug permeability
a Change drug pharmacokinetic characteristics
(clearance and half-life)
a Target receptors for activity or lack of toxicity
I will only address oral dosage forms with
therapeutic advantages, so Commercial only
and, as of today, Target receptors are excluded

I will discuss these various rationales

in terms of BCS and BDDCS.
Many of you may remember my more
detailed discussion of this topic at last
years 7th International Symposium in
Mumbai, but I will give some
background information to bring you
all to the same level.

Probably all of todays attendees will be familiar with the

FDAs Biopharmaceutics Classification System (BCS)
The core idea in the BCS is that an in vitro transport model,
centrally embracing permeability and solubility, with
qualifications related to pH and dissolution, may qualify for
a waiver of in vivo bioequivalence studies.
The objective of the BCS is to: predict in vivo
performance of drug products from in vitro measurements
of permeabilty and solubility.
However, we believe that the framework of the BCS can
serve the interests of the earliest stages of discovery
research in predicting the absorption/disposition of NMEs.

Biopharmaceutical Classification
High
Permeability

Low Solubility

1 Acetaminophen 2

Carbamazepine
Cyclosporine
Digoxin
Ketoconazole
Tacrolimus

Low
Permeability

High Solubility

Chlorothiazide
Furosemide
Methotrexate

Propranolol
Metoprolol
Valproic acid

Cimetidine
Ranitidine

Amidon et al., Pharm Res 12: 413-420, 1995

Biopharmaceutical Classification
High
Permeability

Low Solubility

Class 1

Class 2

High Solubility
High Permeability
Rapid Dissolution

Low Solubility
High Permeability

Low
Permeability

High Solubility

Class 3

Class 4

High Solubility
Low Permeability

Low Solubility
Low Permeability

Amidon et al., Pharm Res 12: 413-420, 1995

BCS High Solubility Criteria

A drug substance is considered
highly soluble when the highest
dose strength is soluble in 250 ml or
less of aqueous media over a pH
range of 1-7.5 at 37C.

BCS High Permeability Criteria

A drug substance is considered to
be highly permeable when the
extent of absorption in humans is
determined to be 90% of an
administered dose based on a mass
balance determination or in
comparison to an i.v. reference dose

High Solubility

High Permeability

Class 1
Abacavir
Acetaminophen
Acyclovirb
AmilorideS,I
Amitryptyline S,I
Antipyrine
Atropine
c
Buspirone
Caffeine
Captopril
ChloroquineS,I
Chlorpheniramine
Cyclophosphamide
Desipramine
Diazepam
Diltiazem S,I
Diphenhydramine
Disopyramide
Doxepin
Doxycycline
Enalapril
Ephedrine
Ergonovine
Ethambutol
Ethinyl Estradiol
FluoxetineI
Glucose

ImipramineI
Ketorolac
Ketoprofen
Labetolol
LevodopaS
Levofloxacin S
LidocaineI
Lomefloxacin
Meperidine
Metoprolol
Metronidazole
MidazolamS,I
Minocycline
Misoprostol
Nifedipine S
Phenobarbital
Phenylalanine
Prednisolone
PrimaquineS
Promazine
Propranolol I
S,
Quinidine I
Rosiglitazone
Salicylic acid
Theophylline
Valproic acid
Verapamil I
Zidovudine

Low Solubility
Class 2
Amiodarone I
S,
Atorvastatin I
S
Azithromycin ,I
Carbamazepine S,I
Carvedilol
Chlorpromazine I
S
Cisapride
Ciprofloxacin S
S,
Cyclosporine I
Danazol
Dapsone
Diclofenac
Diflunisal
Digoxin S
Erythromycin S,I
Flurbiprofen
Glipizide
GlyburideS,I
Griseofulvin
Ibuprofen
Indinavir S
Indomethacin

Itraconazole S,I
Ketoconazole I
LansoprazoleI
Lovastatin S,I
Mebendazole
Naproxen
Nelfinavir S,I
Nifedipine S
Ofloxacin
Oxaprozin
Phenazopyridine
PhenytoinS
Piroxicam
Raloxifene S
Ritonavir S,I
Saquinavir S,I
Sirolimus S
Spironolactone I
Tacrolimus S,I
TalinololS
Tamoxifen I
Terfenadine I
Warfarin

Wu and Benet, Pharm Res 22:11-23 (2005)

High Solubility

Low Permeability

Class 3
Acyclovir
Amiloride S,I
Amoxicillin S,I
Atenolol
Atropine
Bisphosphonates
Bidisomide
Captopril
Cefazolin
Cetirizine
Cimetidine S
Ciprofloxacin S
Cloxacillin
Dicloxacillin S
Erythromycin S,I
Famotidine

Low Solubility
Class 4

Fexofenadine S
Folinic acid
Furosemide
Ganciclovir
Hydrochlorothiazide
Lisinopril
Metformin
Methotrexate
Nadolol
Pravastatin S
Penicillins
Ranitidine S
Tetracycline
Trimethoprim S
Valsartan
Zalcitabine

Amphotericin B
Chlorthalidone
Chlorothiazide
Colistin
Ciprofloxacin S
Furosemide
Hydrochlorothiazide
Mebendazole
Methotrexate
Neomycin

Wu and Benet, Pharm Res 22:11-23 (2005)

Major Routes of Drug Elimination

High
Permeability

Low Solubility

Class 1

Low
Permeability

High Solubility

Class 3

Class 4

Renal & Biliary

Elimination of
Unchanged Drug

Renal & Biliary

Elimination of
Unchanged Drug

Class 2

Metabolism Metabolism

What are the Implications of this Strong

Correlation between Permeability and Metabolism?
a If you know the intestinal absorption (or more
likely a surrogate as Caco-2 permeability, an
in vitro measure) of an NME, you can predict
whether the major route of elimination of the
NME will be metabolism.
aNote that the permeability parameter does not
predict the ability for the NME to enter the liver/
hepatocytes (since a number of non-metabolized
Classes 3 & 4 compounds will be excreted in the
bile), but rather the access to the metabolic
enzymes within the hepatocytes.

Biopharmaceutics Drug Disposition Classification System

BDDCS
Extensive
Metabolism

Low Solubility

Class 1

Poor
Metabolism

High Solubility

Class 3

Class 4

High Solubility
Poor Metabolism

Low Solubility
Poor Metabolism

Class 2

High Solubility
Extensive Metabolism

Low Solubility
Extensive Metabolism

(Rapid Dissolution and

70% Metabolism for Biowaiver)

Distribution of Drugs on the Market

vs. Small Molecule NMEs
High
Permeability

Low Solubility

Class 1

Class 2

Marketed Drugs
~35%
NMEs: 5%

Marketed Drugs
~30%
NMEs: 70%

Low
Permeability

High Solubility

Class 3

Class 4

Marketed Drugs
~25%
NMEs: 5%

Marketed Drugs
~10%
NMEs: 20%

Rationale for Oral NDDS

a Commercial only (no delivery advantages):
marketed drugs--difficult sell in MHO
environment; NMEs may yield patent and/or
anti-generic advantages
a Extended or delayed release to allow more
convenient dosing interval: works for
marketed and NME drugs, all Classes
a Increase drug solubility: Classes 2 and 4
a Increase drug permeability: probably more
successful changing structure for metabolism
a Change drug pharmacokinetic characteristics
(clearance and half-life): works for all

VARIABILITY
The enemy of therapeutics-a decrease in variability is often
the rationale for many NDDS
However, frequently NDDS
increase rather than decrease
variability, particularly ER and
DR dosage forms

People Vary in Their Response to Drugs

For most drugs:30% of people do not respond

10% of people experience
an adverse drug reaction

Drug Response and Variability

DRUG
(Solubility/Permeability)

ENVIRONMENT

GENES

Patient
Nutrition
Smoking
Alcohol
Pollutants
Drug Interactions

Disease

Absorption, Distribution,
Biotransformation
& Elimination

RESPONSE

Monogenic
Polygenic

}Variation

Enzymes
Receptors
Transporters

How should the variability of the two

characteristics that form the bases of
BCS and BDDCS be considered?
Poorly soluble compounds will inherently
result in more variability than highly soluble
compounds
The same relationship with variability does
not necessarily hold for poorly
permeable/poorly metabolized compounds
versus highly permeable/extensively
metabolized compounds

BDDCS is a modification of the FDAs

Biopharmaceutics Classification System.
BDDCS was developed to address DDIs
and transporter-enzyme interplay,
thereby providing a road map for
designing preclinical and Phase 1
clinical studies
However, BDDCS may also be useful in
justifying Class 1 status for marketed
drug products, increasing the number of
drug products eligible for a waiver of in
vivo bioequivalence studies.

Many of you have heard Prof. Gordon Amidon

discuss the $20 M of human studies that he and
Prof. Hans Lennernas had run to determine the
absorption of a group of ~30 drugs that served as a
basis for using metoprolol as the cut-off marker for
absorption greater than 90%
In a late 2006 published paper (Takagi et al., Mol.
Pharm., 3:631-643, 2006) the human permeability
numbers for 29 reference drugs are compiled in a
Journal publication, giving all of us the opportunity
to test various permeability surrogates against the
experimental human values.

Reference Drugs
a -Methyldopa
a Amoxicillin
a Antipyrine
a Atenolol
a Carbamazapine
a Cephalexin
a Cimetidine
a Creatinine
a Desipramine
a D-Glucose
a Enalapril
a Enalaprilat
a Fluvastatin
a Furosemide
a Hydrochlorothiazide

a Ketoprofen
a Levodopa
a Lisinopril
a L-Leucine
a Losartan
a Metoprolol
a Naproxen
a Phenylalanine
a Piroxicam
a Propranolol
a Ranitidine
a Terbutaline
a Valacyclovir
a Verapamil

Ability to Correctly Classify BCS

Permeability for Estimated CLog P and
Log P vs. Metabolism as Compared to
Human Jejunal Permeability Measures
Extensive vs
Poor Metabolism

CLog P

Log P

19 of 29

19 of 27

27 of 29

65.5%

70.4%

93.1%

20 Model Drugs Suggested by FDA

for Use in Establishing Suitability
of a Permeability Method

Permeability Class

Predicted by
CLogP and
Log P

Predicted by
Extent of
Metabolism a

Antipyrine

High (Potential IS candidate)

No

Yes

Caffeine

High

No

Yes

Carbamazepine

High

Yes

Yes

Fluvastatin

High

Yes

Yes

Ketoprofen

High

Yes

Yes

Metoprolol

High (Potential IS candidate)

Yes

Yes

Naproxen

High

Yes

Yes

Propranolol

High

Yes

Yes

Theophylline

High

No

Yes

Verapamil

High (Potential ES Candidate)

Yes

Yes

Amoxicillin

Low

Yes

Yes

Atenolol

Low

Yes

Yes

Furosemide

Low

No

Yes

Hydrochlorthiazide

Low

Yes

Yes

Mannitol

Low (Potential IS candidate)

Yes

Yes

-Methyldopa

Low

Yes

Yes

Polyethylene glycol (400)

Low

Yes

Yes

Polyethylene glycol (1000)

Low

Yes

Yes

Polyethylene glycol (4000)

Low (zero permeability marker)

Yes

Yes

Ranitidine
a
Using 70% as the cutoff

Low

Yes

Yes

Since extent of metabolism correctly predicts high

vs low intestinal permeability for at least 33 of 35
drugs, and may in fact correctly predict all 35
model compounds, Benet and co-workersa propose
the following:

We recommend that regulatory agencies add

the extent of drug metabolism (i.e., 90%
metabolized) as an alternate method for the
extent of drug absorption (i.e., 90%
absorbed) in defining Class 1 drugs suitable
for a waiver of in vivo studies of
bioequivalence.
Benet, Amidon, Barends, Lennerns, Polli, Shah, Stavchansky & Yu.
The Use of BDDCS in Classifying the Permeability of Marketed Drugs,
Pharm. Res., Epub ahead of print, January 31, 2008
a

We propose that the following criteria be used to

define 90% metabolized for marketed drugs:
Following a single oral dose to humans,
administered at the highest dose strength, mass
balance of the Phase 1 oxidative and Phase 2
conjugative drug metabolites in the urine and feces,
measured either as unlabeled, radioactive labeled or
nonradioactive labeled substances, account for
90% of the drug dosed. This is the strictest
definition for a waiver based on metabolism. For an
orally administered drug to be 90% metabolized by
Phase 1 oxidative and Phase 2 conjugative
processes, it is obvious that the drug must be
absorbed.

A major advantage of BDDCS is that drugs

can generally be correctly classified without
running expensive and time consuming
permeability studies in humans.
At this time, BDDCS may not be sufficient for
the regulatory agencies, but it gives scientists a
roadmap for predicting drug disposition and
drug-drug interaction characteristics very early
and with little additional expense.
Lets see further predictions

Cellular and animal studies from our

laboratory over the past seven years
examining transporter-enzyme interplay
led us to make 22 predictions concerning
drug absorption and disposition.
The justification for these predictions, as
well as predictions not specifically
discussed here, may be found in our
January 2005 Pharmaceutical Research
paper
C-Y. Wu and L.Z. Benet. Pharm. Res. 22:11-23 (2005)

Oral Dosing Transporter Effects

High
Permeability/
Metabolism

Low Solubility

Class 1

Low
Permeability/
Metabolism

High Solubility

Class 3

Class 4

Absorptive
transporter effects
predominate (but can
be modulated by efflux
transporters)

Absorptive and
efflux transporter
effects could be
important

Class 2

Transporter
effects minimal in
gut and liver

Efflux transporter
effects predominate in
gut, but both uptake &
efflux transporters
can affect liver

Class 1
highly soluble, high permeability,
extensively metabolized drugs
Transporter effects will be minimal
in the intestine and the liver
Even compounds like verapamil that
can be shown in certain cellular
systems (MDR1-MDCK) to be a
substrate of P-gp will exhibit no
clinically significant P-gp effects in
the gut and liver

Papp Values for Verapamil

in Caco-2 and MDR1-MDCK Cells
(Sahin, Custodio and Benet, AAPS, November 2007)
Cell Line
Caco-2

Concentration

PERMEABILITY (nm/s)
A-to-B

B-to-A

10 nM

65.2 2.9

71.2 3.6

10nM+0.5M GG918

72.4 4.7

73.1 2.0

10 M

93.3 4.1

84.5 2.9

10M+0.5M GG918

91.3 1.2

82.9 2.2

9.1 0.3

127.0 6.1

10nM+0.5M GG918

62.6 0.9

54.1 0.5

10 M

31.5 1.3

130.4 3.8

10M+0.5M GG918

89.4 3.5

80.3 3.7

MDR1-MDCK 10 nM

Class 1 drugs
A major proposition (and probably
the primary advance in knowledge) of
BDDCS is that Class 1 drugs are
not substrates for transporters in
the intestine and liver
(but the BBB and the kidney are not
the gut and liver)

My reaction to the many studies that

use midazolam, diazepam and
verapamil as model substrates?
The science is great and the
correlations are excellent, but so
much of the work is carried out with
Class 1 compounds, where we are
able to ignore transporter effects.
Will the methodology be useful and
reliable when we investigate NMEs?

But in lifecycle management

of existing drugs (NDDS)
Any methodology that increases
solubility of Class 2 drugs (making
them more like Class 1) will not only
increase the driving force
concentration for absorption but also
decrease the importance of efflux
transporters in the intestine

Class 2
poorly soluble, highly permeable,
extensively metabolized drugs

Efflux transporter effects will be important

in the intestine and the liver
In the intestine efflux transporter enzyme
(CYP 3A4 and UGTs) interplay can markedly
affect oral bioavailability
In the liver the efflux transporter-enzyme
interplay will yield counteractive effects to
that seen in the intestine.
Uptake transporters can be important for the
liver but not the intestine.

Current Drug Metabolism

Cover October 2003 Issue

Predicted AUC Changes

for In Vivo - In Situ Studies
Gut
Inhibit P-gp

Inhibit 3A

Inhibit
P-gp+3A

Liver

Rate of Absorption vs Extent of

Absorption in BCS and BDDCS
It is confusing that the FDA and other regulatory
agencies use a rate parameter, permeability, as a
predictor of the extent of absorption ( 90%
absorbed) in BCS. In BDDCS an extent measure
(% metabolized) is used as a predictor of the extent
of absorption
This has led some authors to incorrectly believe that
poorly soluble Class 2 compounds should have
markedly less than 90% absorption. For marketed
Class 2 drug products, almost all show high extent
of absorption because of high permeability. For
marketed Class 2 drugs solubility is rate limiting, not
extent limiting.

Class 3
highly soluble, low permeability,
poorly metabolized drugs
Uptake transporters will be
important for intestinal absorption
and liver entry for these poor
permeability drugs
However, once these poorly
permeable drugs get into the
enterocyte or the hepatocyte efflux
transporter effects can occur.

In lifecycle management of
existing drugs (NDDS)
Prodrugs that increase drug uptake
by intestinal transporters or decrease
efflux by intestinal transporters (here
co-administered substances can also
achieve this objective) can lead to
new, more bioavailable dosage forms

It is generally agreed that animals are

poor predictors of drug metabolism in
man, so we asked the opposite question:

How good are animals at predicting

not metabolized in man?
The Reliability of Animal Models to Predict the Extent
of Metabolism for BDDCS Class 3 Drugs in Humans
Yung-Huei Fu and Leslie Z. Benet (AAPS, Nov. 2007)

For 12 human Class 3 drugs, rats correctly predict

classification for 12 of 12, dogs 10 of 10 and
monkeys 7 of 8

Potential DDIs Predicted by BDDCS

Class 1: Only metabolic in the intestine
and liver
Class 2: Metabolic, efflux transporter and
efflux transporter-enzyme interplay in the
intestine. Metabolic, uptake transporter,
efflux transporter and transporter-enzyme
interplay in the liver.
Class 3 and 4: Uptake transporter, efflux
transporter and uptake-efflux transporter
interplay

Food Effects (High Fat Meals)

Fleisher et al., Clin Pharmacokinet.36(3):233-254, 1999

Low Solubility

High
Permeability

Class 2

Class 1
Fextent
Tpeak

Fextent
Tpeak

Low
Permeability

High Solubility

Class 3

Class 4

Fextent
Tpeak

Fextent
Tpeak

We hypothesize that high fat

meals inhibit transporters
Preliminary results suggest
that the inhibitors are the
monoglycerides found in
high fat meals
(J.M. Custodio, C-Y. Wu and L.Z.Benet,
Adv. Drug Deliv. Rev. 60:717-733, 2008)

High fat meals will have no

significant effect on Fextent for Class
1 compounds since complete
absorption may be expected for high
solubility-high permeability
compounds. However, high fat
meals may delay stomach emptying
and therefore cause an increase in
peak time.

High fat meals will increase Fextent

for Class 2 compounds due to
inhibition of efflux transporters in the
intestine and additional solubilization
of drug in the intestinal lumen. Peak
time can change as a result of a
number of interactive effects, e.g.,
slowing stomach emptying versus
increasing absorption rate via efflux
transporter inhibition.

High fat meals will decrease

Fextent for Class 3 compounds due
to inhibition of uptake transporters
in the intestine.
Peak time would be expected to
always increase due to the
combination of slowing absorption
and stomach emptying.

Sources of Variability as a
Determinant of Candidate Selection
and/or Solved via a NDDS

aSolubility should be a selection/development criteria,

but possibly solved through NDDS
aPermeability can be a criteria for metabolism vs.
not metabolism as the major route of elimination
aBut poorly permeable compounds will not be orally
available if not a substrate for an uptake transporter
aCYP 3A substrate should not in itself be a deselection
criteria
aCYP 3A/Efflux Transporter dual substrate may be a
deselection criteria for oral drugs.

Sources of Variability as a
Determinant of Candidate Selection
and/or Solved via a NDDS

aNTI compounds should be a deselection criteria

aBeing a substrate for P-gp should not be a deselection
criteria, except for the CYP 3A dual substrates.
aBeing a substrate for a polymorphic uptake
transporter (OCT1 > OATPs) may be a deselection
criteria
aCompounds that are substrates for polymorphic CYP
enzymes (2D6 > CYP 2C9 2C19 > 3A5) might be
deselected, but if the Therapeutic Index is wide this
may not be a concern.

Sources of Variability as a
Determinant of Candidate Selection
and/or Solved via a NDDS

aBeing a substrate for an enzyme susceptible to meal,

pesticides and other environmental factors is not a
deselection criteria
aVery short and very long half-lives should be a
deselection criteria, the former solved by an NDDS
aPoor oral bioavailability is a deselection criteria or solved
by an NDDS
aExtent of protein binding should not be a selection criteria
aVolume of distribution should not be a selection criteria
aHigh clearance is less preferred than low clearance, but is
not a deselection criteria; not solved by NDDS

Conclusions
Understanding transporter-enzyme interactions in
terms of the permeability and solubility of drug
compounds offers the potential for predicting:
a. Major routes of elimination
b. Transporter effects of in the gut and liver
c. Food (High Fat Meal) effects
d. Expansion of the regulatory requirement for an
in vivo bioequivalence waiver
e. Enzyme transporter interplay
f. Drug-drug interaction potential and its
relationship to enzyme-transporter interplay

Collaborators & Acknowledgements

aCarolyn Cummins, PhD
aJoseph M. Custodio, BS
aLynda Frassetto, MD
aYong Huang, PhD
aJustine Lam, PhD
aYvonne Lau, PhD
aHideaki Okochi, PhD
aSelma Sahin, PhD
aChi-Yuan Wu, PhD
Funding NIH grants GM 61390, GM 75900, HD 40543 and
an unrestricted grant from Amgen Inc.
Leslie.Benet@ucsf.edu