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

CorrelationThe 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 IVIVC1. 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.

ExampleIn vitro in vivo correlation study of the Leflunomide

loaded MicrospheresDrug : 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.