It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”.
2. In vitro- in vivo correlations (IVIVC)
Criteria for IVIVC
Objective of IVIVC
Levels of IVIVC
BCS for Immediate - Release Drug Product and IVIVC
Expectations.
BCS for Extended - Release Drug Product and IVIVC
Expectations.
Applications of IVIVC.
3. In vitro- in vivo correlations (IVIVC):
In IVIVC, "C" denotes "Correlation", which means "the
degree of relationship between two variables". This term does
not limit a relationship to only the linear type, but allows for
non-linear relationships as well.
It is defined as “the predictive mathematical model that
describes the relationship between in vitro property (such as
rate & extent of dissolution) of a dosage form and in vivo
response (such as plasma drug concentration or amount of
drug absorbed)”.
The main objective of developing and evaluating IVIVC is to
use dissolution test to serve as alternate for in vivo study in
human beings.
4. In vitro- in vivo correlations (IVIVC):
USP definition
“The establishment of rational relationship b/w a biological
property or a parameter derived from a biological property
produced by a dosage form and physicochemical property of
same dosage form”
Conceptually, IVIVC describes a relationship between the in
vitro dissolution / release versus the in vivo absorption.
FDA definition
“A predictive mathematical model describing relationship
between in-vitro property of a dosage form and in-vivo
response.”
5. In vitro- in vivo correlations (IVIVC):
BASIC:-
Simply a mathematical model describing the relationship
b/w in vitro and in vivo properties of drug.
In vitro –in vivo correlation can be achieved using
Pharmacological correlation
“Based on clinical observations”
Semi quantitative correlation
“Based on the drug blood levels or urinary excretion data”
Quantitative correlation
“Arising from absorption kinetics and calculation of in vivo
dissolution rate and absorption rate constants”
6. In vitro- in vivo correlations (IVIVC):
CRITERIA FOR IVIVC
•Successful IVIVC can be developed when in-vitro
dissolution is rate limiting step in absorption and
appearance of drug in in- vivo circulation following oral
or other routes of administration.
•These studies are to be conducted during the early
stages of drug product development in order to select the
most effective formulation and to establish appropriate
dosage regimen.
•The release- controlling excipients in the formulations
should either be identical or very similar.
7. In vitro- in vivo correlations (IVIVC):
OBJECTIVE OF IVIVC
•To reduce the number of human studies during the
formulation development.
•To serve as a surrogate for in vivo bioavailability
•To support biowaivers.
•To validates the use of dissolution methods and
specification settings(This is because the IVIVC includes in
vivo relevance to in vitro dissolution specifications).
•To assist quality control for certain scale-up and post-
approval changes (SUPAC).
• Due to all above objective, such IVIVC leads to
1. Shortens the drug development period,
2. Economizes the resources and
3. Leads to improved product quality.
8. In vitro- in vivo correlations (IVIVC):
Correlations of IVIVC:
1. Correlations based on the plasma level data
2. Correlations based on the urinary excretion data
3. Correlations based on the pharmacologic response
Levels of IVIVC:
Level A: The highest category of correlation. It represents
point to point correlation between in vitro dissolution and in
vivo rate of absorption.
The data treatment involves a two stage Deconvolution
Method.
1. Estimation of the in vivo absorption profile using Wagner-
Nelson or Loo-Riegelman method
2. Comparison of fraction of drug absorbed (Fa) and fraction
of drug dissolved.
9. In vitro- in vivo correlations (IVIVC):
Advantages:
Serves as alternate for in vivo study, change in manufacturing
Procedure or formula can be justified without the need of
additional human studies.
Providing process control and quality assurance
Determining stable release characteristics of the product over
time.
Level B: The mean in vitro dissolution time is compare with
mean in vivo residence time. It is not point to point correlation.
Data can be used for quality control standards.
A predictive model for relationship between summary
parameters that characterize the in-vitro and in-vivo time
course.
10. In vitro- in vivo correlations (IVIVC):
•No point to point correlation
• It compares
1. MDT vitro to MDT vivo,
2. MDT vitro to MRT,
3. In-vitro Dissolution Rate Constant.
This is of limited interest and least useful for regulatory
purposes because more than one kind of plasma curve
produces similar MRT.
Level C: Mathematical model of relationship between the
amount of drug dissolved in-vitro at a particular time and a
summary pharmacokinetic parameter that characterizes in-
vivo time course. (e.g., Cmax, Tmax, T1/2 or AUC).
11. In vitro- in vivo correlations (IVIVC):
It is single point correlation. e.g. t50%, Tmax, Cmax. This
level is only useful as guide for formulation development or
quality control.
Level C correlations can be useful in the early stages of
formulation development when pilot formulations are
being selected.
Lowest correlation level.
Does not reflect a complete shape of plasma concentration
time curve.
MULTIPLE Level C: It relates one or more pharmacokinetic
parameters to the percent drug dissolved at several time points
of dissolution profile and thus may be more useful.
If a multiple Level C correlation is possible, then a Level A
correlation is also likely and is preferred.
12. Biopharmaceutical Classification System (BCS)
for Immediate - Release Drug Product and In
vitro- in vivo correlations (IVIVC) Expectations:
CLASS SOLUBILI
TY
PERMEAB
ILITY
IVIVC Expectations for Immediate-
Release Drug Product
Possibility of
predicting IVIVC
from dissolution
data
I High High IVIVC expected, if dissolution rate
is slower than gastric emptying
rate, otherwise limited or no
correlation.
Yes
II Low High IVIVC expected, if in vitro
dissolution rate is similar to in vivo
dissolution rate, unless dose is very
high.
Yes
III High Low Absorption (permeability) is rate
determining and limited or no
IVIVC with dissolution.
No
IV Low Low Limited or no IVIVC is expected. No
13. Biopharmaceutical Classification System (BCS)
for Extended - Release Drug Product and In vitro-
in vivo correlations (IVIVC) Expectations:
CLASS SOLUBILITY PERMEABILITY Level of IVIVC
I High and site
independent
High and site independent IVIVC Level A expected
II High and site
independent
Dependant on site and
narrow absorption window
IVIVC Level C expected
III Low and site
independent
High and site independent IVIVC Level A expected
IV Low and site
independent
Dependant on site and
narrow absorption window
Little or no IVIVC
Va: Acidic Variable Variable Little or no IVIVC
Vb: Basic Variable Variable IVIVC Level A expected
14. Applications of IVIVC:
A. IVIVC IN DRUG DELIVERY
a) Early stages of drug delivery technology development
b) Formulation assessment
c) Dissolution specifications
d) FUTURE BIOWAIVERS : for minor formulation and process
changes
e) Ivivc parenteral drug delivery : causes of failure of parenteral
IVIVC.
i. Burst Release
ii. Potent Drugs & Chronic Therapy
iii. Limited volume of tissue fluids and Area of absorption at
the site of administration, unlike following the oral route of
administration. Therefore, it is very difficult to specify the in
vitro dissolution conditions that reflect the observed
differences in the in vivo plasma profiles corresponding to
the in vitro release profiles.
15. Applications of IVIVC:
A. NEW IVIVC APPLICATIONS
a) IVIVC for transdermal estradiol systems (novel
pharmaceuticals)
b) Why IVIVC fail for immediate release dosage form
c) Dissolution simulators
i. Gronings model
ii. Sartorius dissolution simulator
iii. Sartorius membrane filter solubility simulator
iv. Sartorius membrane filter absorption simulator.
