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.   Food and Drug Administration (FDA) definitionIVIVC 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 drug absorbed.

1. IN VITRO - IN VIVO
CORRELATION
BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
• In-vivo studies
• Pharmacokinetic parameters
• Correlation levels
 Level A correlation
 Level B correlation
 Level C correlation
 Multiple-level c correlation
 Level D correlation
• Biopharmaceutics classification system (BCS)
• Procedure for in-vitro in-vivo correlation
• Evaluation of predictability of ivivc
ANUSHA NADIKATLA

3.  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.
 Food and Drug Administration (FDA) definition
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 drug absorbed.
IN VITRO - IN VIVO CORRELATION
ANUSHA NADIKATLA

4. • In vitro - in vivo correlation refers to the establishment of
rational relationship between a biological response
produced by a dosage form and a physicochemical
characteristics.
• In recent years, the concept and application of the in vitro-in
vivo correlation (IVIVC) for pharmaceutical dosage forms
have been a main focus of attention of pharmaceutical
industry, academia, and regulatory sectors.
• The main objective of an IVIVC is to serve as a surrogate
for in vivo bioavailability and to support biowaivers.
• IVIVCs could also be employed to establish dissolution
specifications and to support and/or validate the use of
dissolution methods.
ANUSHA NADIKATLA

5. IVIVC could also be employed to establish dissolution specifications and
to support and/or validate the use of :
• Dissolution methods
• Quality control procedures
• Tablet or Capsule disintegration
• Instrumental methods of analysis
• Dissolution Rate Test
• The rate of drug absorption
• Dissolution Profile Parameters
• In Vivo Performance
• Proper In-Vitro Dissolution Rate
• Correlate the data with the bioavailability
Important Purpose: 1. Providing necessary process control
2. Determing stability of dosage form
ANUSHA NADIKATLA

6. • In-Vivo Studies
In-vivo studies deals with the evolution of bioavailability and bio
equivalence of pharmaceutical dosage forms using parameters like AUC,
Cmax etc..
PARAMETERS
1. Drug concentration in plasma at each sampling time
2. Apparent rate constant for elimination
3. Biological half life
4. Urinary excretion rate and amount excreted in urine at infinity
ANUSHA NADIKATLA

7. PHARMACOKINETIC PARAMETERS
1. Mean Residence Time(MRT)
2. Mean Absorption Time(MAT)
3.Cmax/AUC
4.The Peak Occupancy Time(POT)
5.Multiple Dosing
6.Co-efficient of variation
ANUSHA NADIKATLA

8.  Correlation is a measure of relationship between two mathematical
variables or measured data values, which includes the Pearson
correlation coefficient as a special case.
CORRELATION LEVELS
• Five correlation levels have been defined in the IVIVC FDA
guidance.
• The concept of correlation level is 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.
ANUSHA NADIKATLA

9. Level A Correlation
• 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.
• Generally, percent of drug absorbed may be calculated by means of
model dependent techniques such as Wagner-Nelson procedure or
Loo-Riegelman method or by model-independent numerical
deconvolution.
• These techniques represent a major advance over the single-point
approach in that these methodologies utilize all of the dissolution and
plasma level data available to develop the correlations
ANUSHA NADIKATLA

10. It is a point –point relationship between in-vitro data and in-vivo
input rate of drug from dosage form
ADVANTAGES: 1. This is the highest category of relation which act as
a meaningful quality control procedure predictive of invivo performance
of formulation.
2. The invitro curve at stimulated dissolution conditions can serve as
surrogate for invivo performance of formulations.
ANUSHA NADIKATLA

11. ANUSHA NADIKATLA
Mean absorption time is plotted against mean dissolution time for atleast 3 different
preparations.
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).
Level B Correlation
MAT=MRT-MRToral

12. LIMITATIONS
1. It utilizes all data but is non unique as diferent shaped
absorption/dissolution curve could result in same moment value.
2. This correlation alone fails to justify formluations,modification
,manufacturing ,site change ,excipient source change etc.
3. It does not justify the extremes of qualtiy control standards.
ANUSHA NADIKATLA

13. Level C Correlation
• 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
• This is the weakest level of correlation as partial relationship between
absorption and dissolution is established.
• Level C correlations can be useful in the early stages of formulation
development when pilot formulations are being selected.
• Selected parameters are correlated for 3 or more preparations
Eg: Time for 50% dissolution vs AUC,Cmax or Tmax
ANUSHA NADIKATLA

14. 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 be used to justify a
biowaiver.
• A multiple Level C correlation should be based on at least
three dissolution time points covering the early, middle, and
late stages of the dissolution profile.
ANUSHA NADIKATLA

15. Level D correlation
• Level D correlation is a rank order and qualitative analysis and is not
considered useful for regulatory purposes. It is not a formal
correlation but serves as an aid in the development of a formulation or
processing procedure.
• Methodology for developing the Correlation:
• Develop formulation with different release rate such as
slow,medium,fast or a single rate if dissolution is independent.
• Invivo conc. Of plasma BA studies i.e., Wagnernelson method.
• The intensity factor = time for 50% absorption/ time for 50%
dissolution
• Transform T to the corresponding invitro time point applying the
equation T= invivo time/intensity factor.
• Stereochemistry and First pass effect are the factors for developing
correlation ANUSHA NADIKATLA

16. 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 same 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
ANUSHA NADIKATLA

17. BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)
Class Solubility Permeability Absorption rate
control
IVIVC expectations for Immediate
release product
I High High Gastric
emptying
IVIVC expected, if dissolution
rate is slower than gastric
emptying rate, otherwise limited
or no correlations
II Low High Dissolution IVIVC expected, if in vitro
dissolution rate is similar to in
vivo dissolution rate, unless
dose is very high.
III High Low Permeability Absorption (permeability) is rate
determining and limited or no
IVIVC with dissolution.
IV Low Low Case by case Limited
ANUSHA NADIKATLA

18. • The (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
ANUSHA NADIKATLA

19. 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
ANUSHA NADIKATLA

20. PROCEDURE FOR IN-VITRO IN-VIVO CORRELATION
In-Vivo
1.Administer the drug as an oral solution
2.Administer the drug in 3 formulation
3.Apply numericall de conversions
In-Vitro: Dissolution testing of product to asses release rates under various
conditions.
Plasma Level Data: It is established both for a batch of material.
1. Predictive Mathematical Model
2. Quality control tool.
3. Series of Dosage forms.
Drug or Product Requirements for an IVIVC:
• Caution, if narrow therapeutic range
• Linear pharmacokinetics
• Preferably BCS I or II
ANUSHA NADIKATLA

21. Mathematical Techniques :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 on Theory of Linear System Analysis
(Convolution / Deconvolution)
APPLICATIONS:
• Batch to Batch consistency.
• Development of new dosage form.
• Assisting validity.
• Biowaiver for minor formulations and process changes.
ANUSHA NADIKATLA

22. 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.
ANUSHA NADIKATLA

23. 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.
ANUSHA NADIKATLA

24. REFERENCES
1.BIOPHARMACEUTICS AND PHARMACOKINETICS
(D.M.BRAHMANKAR, SUNIL B.JAISWAL).
2.PRINCIPLE AND APPLICATIONS OF BIOPHARMACEUTICS
AND PHARMACOKINETICS (Dr.H.P.TIPNIS, Dr.AMRITA BAJAJ).
3. In VIVO HYDRAULIC CONDUCTIVITY OF MUSCLE (El
Rasheid Zakaria, Joanne Lofthouse, and Michael F Flessner).
4. BIOPHARMACEUTICS AND PHARMACOKINETICS
(Venkateshwarlu).
5 Chen, J.C., M.H. Chiu, R.L. Nie, G.A. Cordell, and S.X. Qius.
Cucurbitacins and cucurbitane glycosides: structures and biological
activities. Nat Prod Rep, 22(3): 386-99 2005
ANUSHA NADIKATLA

25. ANUSHA NADIKATLA