An in vitro – in vivo correlation (IVIVC) is defined as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.

1. In vitro In vivo correlation
(IVIVC)

2. What is IVIVC ?
 An in-vitro in-vivo correlation (IVIVC) has been defined by the U.S. Food and
Drug Administration (FDA) as "a predictive mathematical model describing the
relationship between an in-vitro property of a dosage form and an in-vivo
response".
 Generally, the in-vitro property is the rate or extent of drug dissolution or release
while the in-vivo response is the plasma drug concentration or amount of drug
absorbed
 The United States Pharmacopoeia (USP) defines IVIVC as "the establishment of a
relationship between a biological property, or a parameter derived from a
biological property produced from a dosage form, and a physicochemical property
of the same dosage form".

3. Introduction
 For controlled-release or extended-release formulation, since
dissolution or release of the drug from the formulation is the rate-
limiting step in the appearance of the drug into the systemic circulation,
it is possible to establish a relationship between the release of the drug
in vitro and its release in vivo or its absorption into the systemic
circulation.
 If such correlation exists, then one is able to predict the plasma
concentration time profile of a drug from its in vitro dissolution.

4. Introduction ( cont.)
 The establishment of a predictive IVIVC not only provides you with a better
understanding of the release properties of the drug product but also enables one
to decrease the number of in vivo studies needed to approve and maintain a
drug product on the market resulting in an economic benefit as well as a
decreased regulatory burden.
 It also enables one to set clinically meaningful dissolution specifications based on
the predicted plasma concentration time profile.

5. Evaluating the predictability of the
correlation
 There are two ways in evaluating the predictability of the correlation:
 (1) Internal predictability refers to the ability to predict the pharmacokinetic
profile of the formulations that were used to develop the correlation;
 (2) external predictability refers to the ability to detect the profile of a lot or
formulation that was not used to develop the IVIVC.
 In the United States and in Europe, a bioequivalence study can be waived based on
the IVIVC if the predicted mean AUC and Cmax of the test and reference do not
differ from each by more than 20%

6. Parameters used in IVIVC
 the parameter derived from the biological
property is AUC or Cmax,
 while the physicochemical property is the in
vitro dissolution profile

7. IVIVC Levels
 Five correlation levels have been defined in the IVIVC FDA guidance which are :
 1 - level A
 2- level B
 3- level C
 4- Multiple level C
 5- level D

8. Correlation level A
 This level of correlation is the highest category of correlation and represents a
point-to-point relationship between in vitro dissolution rate and in vivo input rate
of the drug from the dosage form
 percent of drug absorbed may be calculated by means of model dependent
techniques such as Wagner-Nelson procedure or Loo-Riegelmann method or
by model-independent numerical deconvolution .

9. Wagner – nelson
 Used for one compartment model
 Less complicated
 The cumulative fraction of drug absorbed
at time t
Loo- Riegelmann
 Used in multi compartment system
 More complicated
 Fraction absorbed at any time t

10.  Direct mathematical deconvolution, a process of mathematical
resolution of blood level into an input (absorption) and an
output (disposition) component

12. Advantages of Level A correlation
 1- All in vitro dissolution data and all in vivo plasma drug concentration–time
profile data are used . once a Level A correlation is established, an in vitro
dissolution profile can serve as a surrogate for in vivo performance.
 2- A change in manufacturing site, method of manufacture, raw material
supplies, minor formulation modification, and even product strength using
the same formulation can be justified without the need for additional human
studies.
 3- Level A correlation enables the in vitro dissolution test to become meaningful
and clinically relevant quality control test that can predict in vivo drug product
performance.

13. Correlation Level B
 A level B IVIVC utilizes the principles of statistical moment analysis.
 In this level of correlation, the mean in vitro dissolution time (MDTvitro) of the product is
compared to either mean in vivo residence time (MRT) or the mean in vivo dissolution time
(MDTvivo)
 Mean residence time ( MRT): is the average time that molecules of a dosed drug spend in the
body
To understand the basis of MRT, let us start with a simple example. If three molecules of drug A are
injected into an animal, each of these molecules would spend different amounts of time in the system
before being excreted. Let us assume that the time spent is 1, 2, and 3 hr for the first, second, and third
molecules, respectively. Each of these time intervals represents a residence time for each molecule. The
resulting MRT would be 2 hr :
 MRT= total residence time of all drug molecules in the body / total no. of the drug molecules
MRT= 1+2+3/ 3
MRT = 2 hr
 Although a level B correlation uses all of the in vitro and in vivo data, it is not considered to be a
point-to point correlation,
 A level B correlation does not uniquely reflect the actual in vivo plasma level curves. Therefore,
one can not rely upon a level B correlation alone to justify formulation modification,
manufacturing site change, excipient source change

15. Correlation level C
 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. Therefore, it represents a single point correlation and doses not reflect the
entire shape
 This is the weakest level of correlation as partial relationship between absorption
and dissolution is established. Due to its obvious limitations, the usefulness of a
Level C correlation is limited in formulation selection and development

17. Multiple level c correlation
 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
 A multiple Level C correlation should be based on at least three dissolution time
points, early, middle, and late stages of the dissolution profile.
 In general, if one is able to develop a multiple Level C correlation, then it may be
feasible to develop a Level A correlation.

18. Level D correlation
 Level D correlation is a rank order and qualitative analysis and is not considered
useful for regulatory purposes.
 It serves as an aid in the development of a formulation or processing procedure

20. Biopharmaceutic Drug Classification
System

21. References
 Leon Shargel,Andrew Yu.Applied Biopharmaceutics and pharmacokinetics.7th
edition, pg no 437-439.
 Jaber Emami :In vitro - In vivo Correlation: From Theory to Applications ,Isfahan
University of Medical Sciences. 2006.
 A comprehensive guide to toxicology in preclinical drug development . First
edition,2013