In vitro in vivo correlation

PRESENTED BY
ASHWANI GOYAL
2nd SEMESTER
M.PHARMACY
CHITKARA UNIVERSITY
HIMUDA EDUCATIONAL HUB
BAROTIWALA
What is in vitro in vivo correlation
Definition ( According to FDA)

IVIVC is a predictive mathematical model describing the

relationship between an in vitro property of a dosage form and a
relevant 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 dose absorbed.
 What is the need of IVIVC
 Formulation development may require altering formulation
composition, manufacturing equipment and batch sizes.
 In the past when these types of changes are applied to a formulation
 Bioavailability studies would also have to performed in many
instances to ensure that new formulation displayed statistically similar
in-vivo behavior as old formulation.
 This requirement delayed the marketing.
 Added cost and time to the process of formulation optimization.
 Regulatory Authority
The regulatory guidance was developed by the Food and Drug
administration and was based on the scientifically sound research.

Objective:
The regulatory guidance was developed to minimize the need for
additional bioavailability studies as part of the formulation design.
 Correlation
Correlation
The term correlation in pharmaceuticals and related sciences is used
to describe the relationship that exists between variables.

From biopharmaceutical standpoint

It is a relationship between appropriate in vitro release

characteristics and in vivo bioavailability parameters.

 Correlation Levels
Five correlation levels have been defined in IVIVC FDA guidance:

 Level A correlation

 Level B Correlation

 Level C Correlation

 Multiple-level C correlation

 Level D correlation
 Correlation levels

Level A correlation:
 Highest category of correlation.
 Represents a point to point correlation.
 Percentage of drug absorbed is calculated by means of model dependent
techniques such as Wagner-Nelson procedure or Loo regimn Method.
 The purpose of the level A correlation is to define a direct relationship
between in vivo data such that measurement of in vitro dissolution rate
alone is sufficient to determine the biopharmaceutical rate of dosage form.
Level B
 Utilize the principle of statistical moment analysis.

 In this the mean in vitro dissolution time (MDTvitro) of the product is

compared to either mean in vivo resident time (MRT) or the mean in vivo
dissolution time.
 Not represent point to point correlation.

 Since there are number of different in vivo curves that will produce similar
mean residence time values.
 Level B correlation do not uniquely reflect the actual in vivo plasma level
curves.
 Therefore can’t used for quality control purpose.
Mean residence time:

It is the mean time that the drug resides in the body and is calculated
by the following equation:
MRT = AUMC/AUC

Mean in vivo dissolution time:

It is the mean time for a drug to dissolve in vivo from a solid dosage
form and is estimated as:
MDT solid = MRT solid – MRT solution
Level C
 In this one dissolution point i.e. t50%, t90% is compared to one mean
pharmacokinetic parameter such as AUC, tmax or Cmax.
 It represents a single point and does not reflect the entire shape of the
plasma drug concentration curve.
 This is the weakest level of correlation.
 The usefulness is limited in predicting the in vivo performance.
 Level c correlations can be useful in the early stages of formulation
development when pilot formulations have been selected.
Multipoint-Level C
 It relates one or more parameters of interest i.e. Cmax, AUC or any
suitable parameter to the amount of drug dissolved at several time
points of dissolution profile.
 It is based on at least three dissolution time points covering early,
middle and late stages of the dissolution profile.

Level D
 It is a rank order and qualitative analysis and is not considered
useful for the regulatory purposes.
Various parameters used in IVIVC depending
upon the level
 Advantages of IVIVC
1. Minimizes the need for additional bioavailability studies.

2. Minimizes the cost as well as saves time for Formulation optimization.

3. Reduces the bioequivalence studies required for the approval as well
as during scale up and post approval changes.

4. Dissolution test serves as a surrogate for in vivo bioavailability studies

5. Assist in quality control during manufacturing and selecting
appropriate formulation

6. Validates the use of dissolution methods and speccifications.

 Example
In vitro in vivo correlation study of the Leflunomide loaded
Microspheres
Drug : Leflunomide
Use: Treatment of arthritis
Preparation: sustained release microspheres (4 Batches)

In Vitro drug release profile:

 USP Paddle XXI apparatus is used
 Phosphate buffer pH 7.2 is used as dissolution medium.
 Volume of dissolution medium was 900 ml and temp. 37c and paddle
speed was adjusted to 50 rpm
 Sampling was done at an interval of 1hr and 5ml of sample was
withdrawn with the replacement of fresh medium.
 Conc. Was measured at 260nm using UV-Visible spectrophotometer.
In vitro drug release kinetics

In order to study the mechanism of drug release drug release data was
analysed according to zero order, first order and Higuchi square root
equation and Hixon crowell equation.

In Vivo experimentation
 4 groups containing 6 animals each group was used for study.
 Animals were kept at fasting for overnight.
 Microspheres were swllowed easily
 The procedure employed is approved by the animal ethical commettie.
In vitro- iv vivo Correlation ( IVIVC )
 According to FDA guidance four levels of IVIVC have been
described which are levels A, B, C, and multiple C17.
 Here the correlation was established according to Drewe and Grewe
(Drgee A)18.
 The parameters compared were cumulative absorption profile to that
of in vitro dissolution i.e. correlation of the amount of drug dissolved
to that of respective fraction of dose absorbed , time taken for 50%
dissolution to that of 50% absorbed (T50), In vitro dissolution rate
constant (K ) Vs Area Under Curve (AUC) and Mean dissolution
time (MDT) versus mean residence time ( MRT).
RESULTS
 References
1. Emami J. in vitro in vivo correlation: form theory and
applications, Journal of pharmaceutical sciences,9(2): 169-
189,2006
2. Cardot J.M in vitro in vivo correlation: importance of
dissolution in IVIVC, dissolution technologies February 2007
3. Sirisuth Nattee In vivo in vitro correlation definition and
regulatory guidance, international journal of generic drugs
4. Pal . R and Chakraborthy Manas, In vivo in vitro correlation
Study of Leflunomide loaded microspheres, international
journal of pharmacy and pharmaceutical sciences, 1(1), Nov-
dec:2009.