BE
Product
Bioequivalence
Critical Specification for Maintaining Drug
Product Efficacy over Time
Therapeutic Equivalence
BE
Plasma Paradigm vs. Mechanism
Biowaiver
Waiver of In Vivo BE
Studies--Not waiver of BE!
Flux = j = Peff C
The
Th S
Science
i
off BE is
i att the
th Absorption
Ab
ti Site
Sit
For Oral Dosage Form in the GI Tract
High
g So
Solubility,
ub ty, ppH 1-7.5
7.5
Linear and Complete
Absorption
Rapid Dissolution T85
<30 min, pH=1.0,4.6,6.8)
Excipients well
established (not large
doses)
Risk of Therapeutic
Failure Low
Annex 7
Annex 8
page 347
page 391
J=Peff*Cs
10
Mass Transport
C / t + v C =
D 2C + R
BC : jw = DC / t = Peff C
IC : C = 0 (x, y, z) tube at, t = 0
11
Biopharmaceutics Classification
System (BCS): Basis
t
J = (dM / dt )1/ A
= P C P C
P = cm / sec.
Pharmacokinetic
dC / dt = (dM / dt )1/ V
= ka C ka C
ka = 1/ sec
k a = ( S / V ) Pe f f
Software e.g GastroPlus
12
BCS Basis
Drug is absorbed through the intestinal membrane
at a rate that is proportional to the concentration at
the membrane surface. The dissolution of the drug
product in vivo determines the membrane surface
concentration of drug.
13
J=Peff*Cs
14
Solubility
Permeability
High
High
II
L
Low
Hi h
High
III
High
Low
IV
Low
Low
15
V
Vs = V
Volume
l
off S
Solution
l ti
<250 ml,
pH=1-7.5
Highest Dose Strength
Do=Dose/250/C s <1
16
Human Permeability
Huma
an fraction absorbed (%)
100
80
60
40
20
0
0
-4
Human jejunum permeability (x10 cm/s)
10
12
D-glucose
Verapamil
Piroxicam
Phenylalanine
Cyclosporin
Enalapril
Cephalexin
Losartan
Lisinopril
Amoxicillin
Methyldopa
Naproxen
Antipyrine
Desipramine
Propanolol
Amiloride
Mt
Metoprolol
l l
Terbutaline
Mannitol
Cimetidine
Ranitidine
Enalaprilate
Atenolol
Hydrochlorothiazide
Trend line
17
18
Furosemide
Atenolol
Cimetidine
Mannitol
Terbutaline
Amoxicillin (C)
-4
Human jejun
num permeability (x 10 cm/s) at pH 6.5
Hydrochlorothiazide
Lisinopril(C)
Metoprolol
Cephalexin (C)
Enalapril (C)
Propranolol
Phenylalanine (C)
0.1
Desipramine
Antipyrine
Piroxicam
Verapamil (C)
0.01
0.01
Ketoprofen
Naproxen
0.1
10
100
1000
D-Glucose (C)
-6
Metoprolol Absorption
19
Gastric Emptying(Fed)
20
80
50 ml.
200 ml
60
T50 min
40
20
0
I
II
III
Average
21
22
Example: Propranolol
Permeability (Human) = 1.8x10
1 8x10-4 cm/sec
High (Experimental)
Solubility = 2 mg/ml pH < 7.5
Vs =180/2 = 90 ml (< 250 ml): High
High Solubility, High Permeability
Rapidly Dissolving
Class I : In Vitro Dissolution Standard
for BE
BE Dissolution Proposal
Drug Solubility
pH 1.2
Drug Solubility
pH 6.8
Drug
Permeability
High
High
High
II-A
Low
High
High
II-B
High
Low
High
II-C
Low
Low
High
III
High
High
Low
IV-A
Low
High
Low
IV-B
High
Low
Low
IV-C
Low
Low
Low
BCS
Class
Preferred Procedure
>85% Dissolution in 15 min; 30 min, f2., pH =
6.8.
15 min at pH=1.2, then 85% Dissolution in 30
min pH = 6.8;
min.,
6 8; F2>50; 5 points minimum; not
more than one point > 85%.
23
New BE Paradigm
Reduce Unnecessary In Vivo Studies
Increase Oral Product Quality
Based on Scientific Principles and Extendable
E.g. Food Effects
24
Permeability
Absorption Rate
High
High
Low
High
Hi h
High
L
Low
Low
Low
*Since high permeability drugs are rapidly absorbed, maximum plasma concentrations (Cmax),
are indicative of overall AUC and long-duration in vivo studies are not required
High
g So
Solubility,
ub ty, ppH 1-7.5
7.5
Linear and Complete
Absorption
Rapid Dissolution T85
<30 min, pH=1.0,4.6,6.8)
Excipients well
established (not large
doses)
Risk of Therapeutic
Failure Low
25