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05/10/2012

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Part 1 v3
What do we know about the
effectiveness of drug delivery?
! Measure tissue
concentrations
! Measure response
! Derive mathematical
relationships
is a science which attempts to
explain the factors involved
in the absorption, distribution
and clearance of drug
substances in the body:
it encompasses the physical
and chemical properties of
the drug which affects
dissolution and the
permeability and distributive
factors characteristics which
affect efficacy.
The main elements of this lecture are to
link in vitro tests with in vivo tests and we
will be considering methods of acquiring
clinical data appropriate to making the
measurement.
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! A measure
of how much
drug gets into
the systemic
circulation and is
theoretically
available at a
site of action
Time (h)
R
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Action
Biopharmaceutical Fitness
! For an oral drug candidate (that is for 80% of all
drugs in development) to be developed, the
compound must
Dissolve
be absorbed through the gut and
possess sufficient metabolic stability to generate
adequate drug concentrations at the
pharmacologically relevant site so that the desired
action is obtained in a reproducible manner
Formulation
! Formulation-specific behaviour alters the
exposure and time course of absorption
Matrix tablet versus disintegrating tablet
Multiparticulate versus nanoparticulate
Oil versus versus self-emulsifying dispersion
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! Systemic availability represents the amount of
drug that is available to the systemic
circulation and is usually described in terms
of Cmax and AUC.
! Strictly speaking, it is only the total amount
of drug absorbed into the circulation which
describes the bioavailable fraction (F).
! This is measured by the AUC.
AUC Units: !g/ml.h
P
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C
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! Two products are considered to
be bioequivalent when their
concentration vs time profiles ,
from the same molar dose, are
so similar that they are unlikely
to produce clinically relevant
differences in therapeutic and/
or adverse events.
Same drug

Different
formulations

At the same
strength
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A matter of
adequate
therapy
! The release
rate relates
to the Cmax
and Tmax
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Time (h)
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Time (h)
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Time (h)
! Delivery of constructs
! To where they are needed
! At the appropriate time
! For the appropriate period
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! Originally proposed by Amidon and
colleagues (Amidon et al., Pharm. Res. 12:
413-420 , 1995)
! Proposed that Permeability and Dissolution
are the controlling vehicles
! Adoption by the FDA led to waivers on
immediate release products
! Test in vitro mechanistically rather than in
vivo empirically
! Little mechanistic information can be
obtained through a knowledge of AUC or
Cmax
! If two drug products have the same in
vitro dissolution profile under all
lumenal conditions, they will present
the same concentration-time profile at
the intestinal surface and this will lead
to the same extent of absorption
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Objective: In vivo-in vitro
correlation
! Ideal vs real life
! Lag-phase
! Dissolution is faster than
absorption
I
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v
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In vitro dissolution
100%
100%
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! In vivo in vitro correlation.
! An example of the technique:
Time
%

d
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Time
Time
%

d
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80%
P
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C
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Time
T
80%

Cmax or Tmax
1
2 3
4 5
! Solubility Permeability
Class I
High Solubility
High Permeability
Class II
Low Solubility
High Permeability
Class III
High Solubility
Low Permeability
Class IV
Low Solubility
Low Permeability
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! Good SOLUBILTY, Good PERMEABILITY
! Paracetamol
! Quinidine
! Metoprolol
! Caffiene
! Most drugs at low doses
Comment: IVIVC only if gastric emptying is
faster than dissolution
! Tablet may be
completely
dissolved but
since drug is not
absorbed from the
stomach. Gastric
emptying has to
occur to allow
intestinal
absorption
! SOLUBILITY is rate-limiting
! Digoxin (some crystal forms)
! Griseofulvin
! What do you do?
! Select a salt form; mill down drug particles

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! Delays gastric
emptying
! Provides more time
for dissolution
! May bind drugs
! May make a better
solvent system -
emulsion formation
! Tamoxifen (dose 20mg) : poorly soluble in
water






CAN BE MADE MORE ATTRACTIVE BY SOLVENTS
! Alphamethyl DOPA (Aminoacid transporter)
! Atenolol (Paracellular transport)
! Verapamil (Candidate for p-glycoprotein efflux
pump)
! Amoxycillin
! EITHER THERE IS A LIMITED CAPACITY
TRANSPORTER ALLOWING THE DRUGS IN

OR:


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! THE BODY
RECOGNISES
THESE AS
POISONS AND
TRIES TO
THROW THEM
OUT OF THE
CELL
! Frusemide
! Hydrochlorthiazide


Comment: Brickdust but some useful
compounds
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! Fewer clinical trials
! Prediction of behaviour by compedial tests
! In vitro/ in vivo correlation (IVIVC)
cgw
601
Four Tablet variants manufactured to capture the
extreme ends of the variables. Healthy volunteer study

0 8 16 24 32 40 48
Time (h)
0 8 16 24 32 40 48
Time (h)
0 8 16 24 32 40 48
Time (h)
0 8 16 24 32 40 48
Time (h)
Variant 1 Variant 3
Variant 2 Variant 4
Courtesy Tahseen Mirza 2010, Saudi Pharmaceutical Conference
The problems of an over-discriminatory
method..
Courtesy Tahseen Mirza 2010, Saudi Pharmaceutical Conference
0 2 4 6 8
10 12 Time (h)
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The 3
Dimensionless
Numbers
MATHS
ABSORPTION
NUMBER
DOSE
NUMBER
DISSOLUTION
NUMBER
! Defined as the ratio of the permeability
and the intestinal radius multiplied by
the residence time (the transit time).

! An = =t
abs
-1
t
res
= t
res
/t
abs

! Peff/R is the effective residence time
! So lets try and use it
Peff
R
t
res
! Vila Int J Clin Pharmacol Ther Toxicol. 1992 Aug;30(8):280-6.
! In the small intestine, the absorption rate
constants, Ka, at pH 6.2 ranged between
0.38 h-1 for atenolol and 4.28 h-1 for
penbutolol. In the colon, the rate of drug
absorption at pH 7.5 ranged between
0.12 h-1 for atenolol and 2.15 h-1 for
penbutolol.
! An = t
res
/t
abs
=

3/0.38 = 7.9 in the small
intestine
! = 4/0.12 =33 in the colon
! High An Poorly absorbed, Low An well absorbed
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ProblemsNo problems
! Ratio of the residence time to the dissolution
time which itself is
! A function of the equilibrium solubility
! A function of diffusivity
! A function of density
! A function of the initial particle radius
! Simplifies to t
res
/ t
diss
! Ideally 1 or greater
! In the case of solid dosage forms, a combination of
inadequate solubility or diffusivity, or excessive
particle size or density can increase the time
needed for full dissolution and reduce this ratio
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Time (h) Average Drug
released (%)
2 <30

4 30-55
8 55-80
12 65-90
! The dose number is the ratio of the dose to the
amount of drug that will dissolve in 250 mL of test
solution at the lowest solubility within the pH range
1 to 8.
! Ideally, this ratio should be below 1 if full
dissolution is to be possible in principle. Obviously,
higher doses will raise the ratio and make good
absorption less likely
Mo / Vo
Css
Example: Css= 0.4 mg mL
200 mg dose/250 mL = 0.8 mg mL =0.8/0.4 = 2
! Case 1
! Dose that is administered= 50 mg
! Volume = 250 ml
! Css Solubility of drug = 0.2 mg ml
-1
! =0.2/0.2 - DOSE SHOULD DISSOLVE IN ADMINISTERED
FLUID

! Case 2
! Dose = 200 mg
! Volume = 100 ml
! Solubility of drug = 0.01 mg ml
-1
! =2/0.01 = 200
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! Weak acids
! Mefamic acid 500 litres
! Troglitazone 100 litres

! Neutral compounds
! Danazol 200 litres
! Atavaquone 1,785 litres
! Felodipine 10 litres
Dressman EDAN 28March 04
! Doesnt make sense because
aqueous solubilities do not reflect
what is going on in the gut...
! Felodipine
! Dose 10 mg
! Solubility in water 1 !g ml
-1

! Solubility in simulated intestinal fluid (fasting) 49
!g ml
-1
= 204 ml
! Solubility in simulated intestinal fluid (fed) 237 !g
ml
-1
= 42 ml
! Food solves the problem easily
Dressman EDAN 28March 04
05/10/2012
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ORANGE
ZONE
D:S 250 -1000
ml

Simple
approaches
e.g.
micronisation
may sufce
GREEN ZONE
D:S < 250 ml

Conrm with
Biorelevant
Media






RED ZONE
D:S > 1000 ml






Confirm with
Biorelevant
Media
Simple
approaches
e.g.
micronisation
may suffice
Formulation will
require expertise
and creativity
Dressman EDAN 28March 04
! Slow entry
! Efflux and metabolism
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The Grapefruit Juice Story began 10 years
ago, during experiments designed to study
interactions between a Ca
2+
channel antagonist
felodipine and alcohol. Grapefruit juice was
included in the experiments as it masked the
taste of the alcohol better than any other fruit
juice tested. As a result of this, grapefruit
juice became a subject to a study itself, as it
was discovered to change the effects of
felodipine significantly on its own.
NARINGIN
Gives juice its
characteristic
taste and colour
Most
prevalent Flavonoid
found in grapefruit
juice
Has no direct effect on
human cytochrome P450
enzymes

Its metabolite
is a potent
inhibitor of the CyP3A4
enzyme - resulting in
The Grapefruit Juice
Effect


Is hydrolysed to its
metabolite NARINGENIN
in the small intestine
after oral administration

Here are some examples of drugs whose effects
are potentiated by the action of Grapefruit
Juice.
Ca
2+
channel
blockers
eg. Felodipine.

Antihistamines
eg. Terfenadine.
Immunosuppresant
eg. cyclosporin
other drugs include:
Benzodiazepines
Oral contraceptives
HIV-protease inhibitors
GRAPEFRUIT JUICE
POTENTIATES THE
EFFECTS OF...
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! Multidrug resistance:
MDR
! Active in the apical cells
of the gut
! Restricts the rate of entry
of verapamil and
cyclosporine
! Works in concert with
CyP3A4