IVIVC is a predictive mathematical model describing the relationship between an in vitro property of a dosage form and a relevant in vivo response.

1. IVIV correlation
PhD student : Aqeel Akab Aljanabi
Department of pharmaceutics
Tehran university of medical science

2. IVIVC
Food and Drug Administration (FDA )
is a predictive mathematical model describing the relationship
between an in vitro property of a dosage form and a relevant
in vivo response.
United State Pharmacopoeia (USP)
The establishment of a rational relationship between a
biological property, or a parameter derived from a
biological property produced by a dosage form, and a
physicochemical property or characteristic of the same
dosage form.

3. Objectives 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 objectives, such IVIVC leads to :
• Shortens the drug development period,
• Economizes the resources
• Leads to improved product quality

4. Approaches to develop IVIVC models
• Based upon the ability of the
correlation to reflect the
complete plasma drug level-
time profile which will result
from administration of the
given dosage form, there are
four levels of IVIVC

5. • The highest category of correlation and represents a point-to-
point relationship between in vitro dissolution rate and in vivo
absorption rate of the drug from the dosage form.
• It can serve as an alternative for in vivo performance. The changes
can be justified without the need for additional human studies.
Level A Level B Level C Multi Level C

6. • Utilizes the principal of statistical analysis.
• In this level , the mean in vitro dissolution time
(MDT vitro) compared to either mean in vivo
residence time (MRT) or the mean in vivo
dissolution time (MDT).
• Limitaion It is not considered to be a point-to-point
correlation, since there are a number of different in
vivo curves that will produce similar mean residence
time values. .
LevelA Level B Level C Multi Level C

7. • In this level of correlation, one dissolution time point
(t50%, t90%, etc.) is compared to one mean
pharmacokinetic parameter such as AUC, tmax or
Cmax.
• Limitaion This is the weakest level of correlation
since it represents a single point correlation and
doses not reflect the entire shape of the plasma
drug concentration curve.
• Level C correlations can be useful in the early stages
of formulation development when pilot
formulations are being selected. Biowaiver of an in
vivo bioequivalance study is generally not possible
LevelA Level B Level C Multi Level C

8. • A multiple level C correlation relates one or several pharmacokinetic
parameters of interest (Cmax, AUC, or any other suitable parameters) to the
amount of drug dissolved at several time points of the dissolution profile.
• This correlation may be used to justify a biowaiver.
LevelA Level B Level C Multi Level C

9. IMPORTANT CONSIDERATIONS IN
DEVELOPING A CORRELATION
• When the dissolution is not influenced by factors such as pH, surfactants,
osmotic pressure, mixing intensity, enzyme, ionic strength, a set of
dissolution data obtained from one formulation is correlated with a
deconvoluted plasma concentration-time data set.
• If one or more of the formulations (highest or lowest release rate
formulations) may not illustrate the relationship between in vitro
performance and in vivo profiles compared with the other formulations, the
correlation is still valid within the range of release rates covered by the
remaining formulations

10. Biopharmaceutical classification system
(BCS)
• The biopharmaceutical classification system (BCS) is a drug development
tool that allows estimation of the contribution of three fundamental
factors including dissolution, solubility and intestinal permeability, which
govern the rate and extent of drug absorption from solid oral dosage
forms.
• BCS is also a fundamental guideline for determining the conditions under
which IVIVCs are expected.
• It is also used as a tool for developing the in-vitro dissolution specification

11. Class
Ⅰ
Ⅱ
Ⅲ
Ⅳ
Solubility
High
Low
High
Low
Permeability
High
High
Low
Low
IVIV expectation
For intermediate
release product
IVIV expected
IVIV expected
Absorption is
rate limiting step
IVIV is
unexpected
Possibility of
predicting IVIV
from dissolution
data
Yes
Yes
No
No
BCS classification system
For immediate release drug product and IVIV expectation

12. BIOAVAILABILITY STUDIES FOR DEVELOPMENT
OF IVIVC
•A bioavailability study should be performed to
characterize the plasma concentration versus time profile
for each of the formulation.
• Bioavailability studies for IVIVC development should be
performed with sufficient number of subjects to
characterize adequately the performance of the drug
product under study

13. MathematicalTechniques :
Assessment
of in vivo
drug release
or absorption
from plasma
profiles
MODEL-DEPENDANT: based on the mass balance
among the pharmacokinetic Compartments (e.g.
Wagner-Nelson, Loo-Riegelman)
MODEL-INDEPENDENT; based onTheory of Linear
System Analysis (Convolution / Deconvolution)

14. EVALUATION OF PREDICTABILITY OF IVIVC
• An IVIVC should be evaluated to demonstrate that predictability of in vivo
performance of a drug product from its in vitro dissolution characteristics is
maintained over a range of in vitro dissolution release rates and
manufacturing changes.
• Depending on the intended application of an IVIVC and the therapeutic
index of the drug, evaluation of prediction error internally and/or externally
may be appropriate.
• External predictability evaluation is not necessary unless the drug is a
narrow therapeutic index, or only two release rates were used to develop
the IVIVC, or, if the internal predictability criteria are not met i.e. prediction
error internally is inconclusive.

15. • INTERNAL PREDICTABILITY
All IVIVCS should be studied regarding internal predictability. One
recommended approach involves the use of the IVIVC model to predict each
formulation's plasma concentration profile (or Cmax and/or AUC for a multiple
Level C IVIVC) from each respective formulation's dissolution data.
• EXTERNAL PREDICTABILITY
Most important when using an IVIVC as a surrogate for bioequivalence is
confidence that the IVIVC can predict in vivo performance of subsequent lots
of the drug product. Therefore, it may be important to establish the external
predictability of the IVIVC. This involves using the IVIVC to predict the in vivo
performance for a formulation with known bioavailability that was not used in
developing the IVIVC model

16. Limitations
•Cannot be applied to all dosage forms.
•Its unable to accurately estimate the rate of drug
absorption in vivo.

17. •Overall, IVIV correlation acts as an alternative for
in vivo bioavailability .Also, it allows to setting and
validating a more meaningful dissolution method
and qualification. In addition to its assistance for
certain scale up and post approval changes.
Conclusion