Bioequivalence Testing for Locally

Acting Gastrointestinal Drugs:

Scientific Principles

Gordon L. Amidon, Ph.D.

Professor of Pharmaceutical Sciences
College of Pharmacy
The University of Michigan
 Bioequivalence (BE): Orange Book

the rate and extent of absorption of the

test drug do not show a significant
difference from the rate and extent of
absorption of the reference drug when
administered at the same molar dose of the
therapeutic ingredient under similar
experimental conditions in either a single
dose or multiple doses;
BE: The Crucial Market Place
Pharmaceutical Standard
Locally Acting Drugs: Orange Book

Where these above methods are not applicable

(e.g., for drug products that are not intended to be
absorbed into the bloodstream), other in vivo or in
vitro test methods to demonstrate bioequivalence
may be appropriate.
 BE Testing GI Drugs

Plasma concentration may not reflect the therapeutic

effect, while it may indicate safety.
Concentration at the local GI tract site is not easily
measured directly.

Key Scientific Principles for the Following Issues:

Role of Pharmacokinetic (PK) Studies
Role of In Vitro Studies
Role of Clinical Studies
 Pharmacokinetic BE

Formulation
PK Sample
Performance

Dose Plasma
Dissolution Absorption
concentration

Efficacy at the site of action

Safety

Systematically acting drugs

Classical BE
BE Paradigm
 BCS approach to BE

If two drug products, containing the same

drug, have the same concentration time
profile at the intestinal membrane surface
then they will have the same rate and extent
of availability at the site of action.
If two drug products have the same in vivo
dissolution profile under all luminal
conditions, they will have the same rate and
extent of availability at the site of action.
 BCS Essential Idea
t
M (t ) P C dAdt
0 A
Maximum Absorption Rate
Transport
J (1/ A)(dM / dt ) Max Peff Cs
PK
dC / dt (1/ V )dM / dt kaCs
(V / A)dC / dt (V / A)ka Cs
Drug Absorption: Ficks 1st Law
Applied to a Membrane

j (1 / A)dM / dt Dmem dCmem / dx

Dmem K (Caq / x)
Peff C
 Diffusion vs.Pharmacokinetic
Views
Diffusion Pharmacokinetic

J (dM / dt )1/ A dC / dt (dM / dt )1/ V

P C P C ka C ka C
P cm / sec. ka 1/ sec
ka ( S / V ) Peff

Software e.g GastroPlus

Drug Absorption at any Site
dM/dt(1/A) = Peff*C
dM/dt (1/A)at that point
Peff(x,y,z,t, excipients) at that point
May be affected by drug and excipients if in
direct contact
C(x,y,z,t)at that point
BE Paradigm Shift
 GI Drugs

Formulation
PK Sample
Performance

Plasma
Dose Dissolution Absorption concentratio
n

Efficacy at the site

Safety
of action

Locally acting GI drugs: disconnection between the PK

sample and the effectiveness
 BE of GI Local Drugs

Plasma concentration is down stream from site of

clinical effect.
Local site of action in GI Tract.
Dissolution and transit in vivo controls presentation of
drug to site of action
Low Permeability Drugs
Low Systemic Availability
 Role of In Vitro Study
For locally GI acting drugs,
In vivo dissolution is the key determinant
of presentation of drug to site of action.
In vitro dissolution testing must cover the
range of the in vivo variables.
Biowaiver for BCS I drugs is applicable
to GI locally acting drugs (GE Limited).
 In Vitro BE Dissolution

pH dissolution profile:
Suitable for pH dependant dissolution through a pH
dependant coating
Surfactant changes:
Suitable for poorly soluble compounds
Dissolution pH Testing
Gastric pH and time
Small Intestinal pH range
Similar (f2) profiles
 Role of in vitro Studies:
Is Biowaiver applicable?

Biowaivers for BCS class I drugs in immediate release

solid oral dosage forms are well established.
If two drug products, containing the same drug, have
the same concentration time profile at the intestinal
membrane surface then they will have the same rate
and extent of availability at the site of action.
If two drug products have the same in vivo dissolution
profile under all luminal conditions, they will have the
same rate and extent of availability at the site of action.
 Example of Mesalamine
biopharmaceutical properties

Three major factors to consider for

developing an in-vitro BE test:
COOH 1. Solubility:
OH
- 1.996 mg/mL at 20C
- 3.216 mg/mL at 30C
- High solubility based on 250 mL volume
H2 N and 500 mg dose
2. Permeability: May be less important as
mesalamine is acting locally in GI tract.
Molecular structure of Mesalamine
3. Dissolution: Reflect in-vivo dissolution to
ensure BE.
 Examples of Mesalamine Formulations
PBS
pH 6.8
SGF

PBS PBS
pH 7.2 pH 7.8

Dissolution of mesalamine formulations in SGF and phosphate buffers pH 6.8, 7.2 and 7.8

M.W. Rudolph, S. Kevin, T. E. Beckert, H. Petereit and J. B. Dressman,

Eur. J. Pharm. Biopharm. 51 (3): 189-190, 2001.
 Role of Clinical Studies
Conventional comparative clinical studies
are used when PK/PD approaches are infeasible.
are expensive and insensitive to formulation difference.

Innovative clinical studies

measure the concentration along the GI mucosal lining.
are sensitive to formulation changes and reflective of
in-vivo dissolution.
are still expensive.
 Topic Questions
? For locally acting GI drugs is PK, if measurable, an
in vivo test sensitive to formulation performance and
useful as a part of a determination of bioequivalence?
? Are there any drug specific issues that would aid
FDA in interpreting the results of a PK study on a GI
acting drug with respect to a conclusion about
bioequivalence?
? When is it possible to use dissolution testing alone to
demonstrate BE of GI acting drug products?
? When should comparative clinical studies be
conducted to demonstrate BE?
? When the food-effect studies be considered?
BE Paradigm Shift
End