Invitro invivo correlation

1. IN VITRO-INVIVO CORRELATION
(IVIVC)
PRESENTED BY,
VINEETHA K
DEPT. OF PHARMACEUTICS
1ST M. PHARM
NGSMIPS

2. CONTENTS:
 Introduction.
 Definition.
 Approaches for developing correlations.
 Need for IVIVC.
 Levels of IVIVC.
 IVIVC methods.
 Applications of IVIVC.

2

3. INTRODUCTION:
 The therapeutic efficacy of a pharmaceutical
formulation is governed by factors related to:
 In vitro dissolution characteristics of the drug
&
 Its in vivo bioavailability.
 This inherent interdependency within the
drug-patient biosystem is the major concern
that underlines the importance of in vitro/in
vivo correlation studies.
3

4.  In vitro dissolution refers to the process of
dissolution(release) of drug from dosage
form as measured in an in vitro dissolution
apparatus.
 In vivo dissolution refers to the process of
dissolution of drug in the gastrointestinal
tract.
 Correlation is a relationship between in vitro
dissolution rate and in vivo input(absorption
rate) as used in bioequivalence guidance.
4

5.  Bioavailability implications of dissolution
should never be accepted on faith, rather it has
to be proved through carefully designed in
vitro-in vivo correlation studies.
 The need for such comparisons has been
recognized since early 1960’s & the regulations
on bioavailability and bioequivalence were
issued by the FDA in 1977.
 Long back, Wagner had stated that,
“Future research in dissolution rate should be
directed mainly towards establishing
correlation of in-vitro data with in-vivo
data.”
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6. DEFINITION:
 In IVIVC, "C" denotes "Correlation", which means "the degree
of relationship between two variables". This term does not limit
a relationship to only the linear type, but allows for non-linear
relationships as well.
 Conceptually, IVIVC describes a relationship between the in
vitro dissolution / release versus the in vivo absorption.
 FDA had defined IVIVC as “A predictive mathematical model
describing relationship between in-vitro property of a dosage
form and in-vivo response.”
 In-vitro properties are rate or extent of drug released under a
given set of conditions. In-vivo properties are plasma drug
conc. expressed in terms of Cmax, AUC.
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7. APPROACHESFORDEVELOPING
CORRRELATIONS:
The basic approaches by which correlations
between dissolution testing and bioavailability
are:
 Predicting the mathematical model(linear
relationship) between the in vitro dissolution
testing and existing bioavailability data.
 Modifying the dissolution methodology on the
basis of existing bioavailability and clinical
data.
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8. NEEDFORIVIVC
 Theoretically worthwhile, but Clinical
approach is a poor tool for accurate
measurement of bioavailability.
 Determination of drug level at the site of
administration.
 Urinary excretion analysis of drug is
meaningful for establishing IVIVC but
complicated pharmacokinetic considerations.
 Thus it is generally assumed that blood
(serum/plasma) level measurements give a
better assessment of bioavailability and
bioequivalence.
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9. Some of the often used quantitative linearin vitro-in
vivo correlation are:
 Correlations based on the plasma level
data: Here linear relationships between
dissolution parameters and plasma level data are
established.
 Correlations based on the urinary
excretion data: Here, dissolution parameters
are correlated to the amount of drug excreted
unchanged in the urine, cumulative amount of
drug excreted as a function of time, etc.
 Correlations based on the
pharmacological Response: An acute
pharmacological effect such as LD50 in animals
is related to any of the dissolution parameters.
9

10.  Statistical moments theory can also be used to
determine the relationships such as mean
dissolution time (in vitro) versus mean residence
time (in vivo).
 Though examples of good correlations are many,
there are instances when positive correlation is
difficult or impossible.
 E.g., in case of corticosteroids, the systemic
availability may not depend upon the dissolution
characteristics of the drug.
 Several factors that limit such a correlation
include dissolution methodology,
physicochemical properties of the drug,
physiological variables.
10

11. LEVELSOFIVIVC:
 There are four levels of IVIVC that have been
described in the FDA guidance, which include levels
A, B, C, and multiple C.
 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.
Level A
Level B
Level C
Multiple C Figure 1: levels
of correlations. 11

12. LEVELACORRELATION:
• Point-to-Point relationship
• Usually Correlations are linear, and no formal
guidance on the non-linear IVIVC.
• The data treatment involves a two stage
Deconvolution Method.
• Estimation of the in vivo absorption profile
using Wagner-Nelson or Loo-Riegelman
method
• Comparison of fraction of drug absorbed (Fa)
and fraction of drug dissolved (Fd) in-vitro to
obtain a linear correlation.
• PURPOSE – DEFINE DIRECT RELATIONSHIP
12

13. • Formulations showing
Level A correlation
require no additional
human studies to justify
change in manufacturing
site, raw material
supplier or minor
formulation changes.
• Most informative and
very useful from a
regulatory perspective.
Figure 2: Correlation between
percent theophylline dissolved
in vitro and percent
theophylline absorbed after
administration of extented
release product.
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14. Importance of level A correlation
 The in vivo dissolution serves as in vivo
indicating quality control procedure for
predicting dosage form performance.
 Determining stable release characteristics of
the product over time.
 A point to point correlation is developed.
14

15. LEVELBCORRELATION:
 A predictive model for relationship between summary
parameters that characterize the in-vitro and in-vivo
time course.
 It compares
1) MDT vitro to MDT vivo,
2) MDT vitro to MRT,
3) In-vitro Dissolution Rate Constant (kd) to Absorption
Rate Constant (ka).
 Comparison using Statistical moment analytical method.
 This type of correlation uses all of the in vitro and in vivo
data.
 This is of limited interest and least useful for regulatory
purposes because more than one kind of plasma curve
produces similar MRT.
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16. LEVELBCORRELATION:
Figure 2: Correlation of mean in vitro dissolution
time(MDT) and mean absorption time(MAT).
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17. Limitations
 Level B correlation is not unique, because MRT
remains same, though the shape of in vivo curves are
different.
 Therefore it fails to justify the formulation
modifications.
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18. LEVELCCORRELATION:
 Predictive mathematical model which
relates one dissolution time point
(e.g.t50%) to one pharmacokinetic
parameter that characterizes in-vivo time
course. (e.g., Cmax, Tmax, T1/2 or AUC).
 Level C correlations can be useful in the
early stages of formulation development
when pilot formulations are being
selected.
 Lowest correlation level
 Does not reflect a complete shape of
plasma concentration time curve.
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19. LEVELCCORRELATION:
Figure 3: correlation between mean dissolution time and AUC of
plasma drug time curve of four formulations.
19

20. MULTIPLELEVELCCORRELATION:
• It relates one or more pharmacokinetic
parameters to the percent drug dissolved at
several time points of dissolution profile
and thus may be more useful.
• 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.
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21. LEVELDCORRELATION:
 It is not a formal correlation but it is a
semi quantitative (qualitative analysis)
and rank order correlation and is not
considered useful for regulatory purpose.
 Serves as an aid in the development of a
formulation or processing procedure.
21

22. LEVEL IN VITRO IN VIVO
A Dissolution curve Input(absorption curves)
B Statistical moments: mean
dissolution time(MDT)
Statistical moments: mean
residence time(MRT), mean
absorption time(MAT) .
C Disintegration time, time to
have 10%, 50%, 90% dissolved,
dissolution rate, dissolution
efficiency(DE)
Maximum observed
concentration( cmax ),
observed at time( tmax ),
absorption constant(ka), time
to have 10,50,90% absorbed,
AUC(total or cumulative)
A: one-to-one relationship between in vitro and in vivo data, e.g., in vitro
dissolution vs. in vivo absorption
B: correlation based on statistical moments, e.g., in vitro MDT vs. in vivo MRT
or MAT
C: point-to-point relationship between a dissolution and a pharmacokinetic
parameter, e.g., in vitro T50% vs. in vivo T max, Multiple C: relationship between
one or several PK parameters and amount dissolved at several time points.
Table 1: Various parameters used in IVIVC depending on the level.
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23. IVIVC MODELS.
 It is generally assumed that absorption and
dissolution have a linear relationship hence
dissolution and absorption characteristics of a
drug are commonly shown interchangeably.
 It is to be noted that one should be able to
establish drug profiles with dissolution profiles
combined with the pharmacokinetic
characteristics of the drug.
 This process of obtaining a drug profile from
dissolution results is known as convolution.
 The opposite of this, i.e., obtaining or extracting
a dissolution profile from a blood profile, is
known as deconvolution.
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24. Schematic representation of deconvolution and
convolution processes. Convolution is process of
combined effect of dissolution and elimination of
drug in the body to reflect blood drug
concentration-time profile (right to left). On the
other hand, extracting dissolution profiles from
blood drug concentration-time profile is known
as the deconvolution process (left to right) 24

25. IMPORTA
NCE
OF
IVIVC
To reduce
the
number of
human
studies
As a
surrogate
of in vivo
bioavailab
ility
To set the
dissolution
specificatio
ns
Developme
nt of
drug
delivery
systems.
To support
biowaivers
for
bioequivale
nce
testing
Research
tool
for
Formulation
Screening
To assist
quality
control
for certain
SUPAC.
To explore
the
relationsh
ip
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26. APPLICATIONOFANIVIVC:
1. Application in drug delivery system:
 Various rate controlling technologies are used as the
basis for Modified release dosage forms e.g. Diffusion-
dissolution, matrix retardation, osmosis, etc. to control,
and prolong the release of drugs, for the administration by
oral or parenteral route .
 The novel drug delivery systems have been developed
such as OROS, liposomes, niosomes, pharmacosomes,
microspheres, nanoparticles, implants, insitu gelling
system, parenteral depots, etc. as a substitute for
conventional dosage forms.
 The obvious objective of these dosage forms is to achieve
zero order, long term, pulsatile delivery.
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27. 2.In early stages of drug delivery
technology development
 The most crucial stage in the drug development is
drug candidate selection.
 Such selection is primarily based on the drug
“developability” criteria, which include
physicochemical properties of the drug and the
results obtained from preformulation, preliminary
studies involving several in vitro systems and in vivo
animal models, which address efficacy and toxicity
issues.
 During this stage, IVIVC (exploring the relationship
between in vitro and in vivo properties) of the drug in
animal models provide an idea about the feasibility of
the drug delivery system for a given drug candidates.
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28. 3.Formulation assessment: In vitro
dissolution :
 A suitable dissolution method that is
capable of distinguishing the performance
of formulations with different release rates
in vitro and in vivo is an important tool in
product development.
 Depending on the nature of the correlation,
further changes to the dissolution method
can be made.
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29. 4. Dissolution Specifications:
 Modified-release dosage forms typically
require dissolution testing over multiple
time points, and IVIVC plays an important
role in setting these specifications.
 Specification time points are usually
chosen in the early, middle, and late stages
of the dissolution profiles.
 In the presence of IVIVC, wider
specifications may be applicable based on
the predicted concentration-time profiles
of test batches being bioequivalent to the
reference batch.
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30. 5.Future biowaivers.
 Frequently, drug development requires
changes in formulations due to a variety of
reasons, such as unexpected problems in
stability, development, availability of
better materials, better processing results,
etc.
 Having an established IVIVC can help
avoid bioequivalence studies by using the
dissolution profile from the changed
formulation, and subsequently predicting
the in vivo concentration-time profile .
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31. 6.IVIVC parenteral drug delivery
 IVIVC can be developed and applied to
parenteral dosage forms, such as controlled-
release particulate systems, depot system,
implants etc. that are either injected or
implanted.
 However, there are relatively fewer successes
in the development of IVIVC for such dosage
forms, which could be due to several reasons.
 Sophisticated modeling techniques are
needed to correlate the in vitro and in vivo
data, in case of burst release which is
unpredictable and unavoidable.
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32. Some limitations in IVIVC:
1. Complexity of the drug absorption: A
number of biological factors influence the
drug absorption. These factors cannot be
mimicked in in vitro.
2. Weakness of the dissolution design:
Being in vitro model, it is natural to have
certain limitations. The physics of tabletting
as well as nature of mechanical and
hydrodynamic forces that operate during
dissolution are not well understood.
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33. CONCLUSION:
 The pharmaceutical industry has been striving to find a ways to
saving precious resources in relevance to the budgets and
increasing cost of drug development.
 IVIVC is a tool applied in various areas and stages of drug
development to find a place in the regulatory bodies around the
world.
 IVIVC can serve as surrogate for in vivo bioavailability and to
support biowaivers also allows setting the dissolution specification
and methods.
 The substitute of expensive clinical trials with the use of IVIVC is
perhaps the most important feature of IVIVC.
 From the regulatory point of view IVIVC can assist certain scale-
up and post-approval changes.
 IVIVC principles have been mostly applied to oral products, there
exists a need to develop methodologies and standards for non-oral
delivery systems, to develop more meaningful dissolution and
permeation methods.
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34. REFERENCE:
1.Shargel L, AndrewYU. AppliedBiopharmaceuticsand
Pharmacokinetics.2nd Edn.Singapore:The McGraw-Hill
Companies;2012.380-386p.
2. SubrahmanyamCVS. Biopharmaceuticsand
Pharmacokinetics-conceptsandapplication.1st Edn.Delhi:
Vallabh Prakashan; 2010.164p.
3.Brahmankar DM, JaiswalSB. Biopharmaceuticsand
Pharmacokinetics-A treatise.2nd Edn.Delhi:Vallabh
Prakashan;2009.332p.
4. Sakore S, Chakraborty B. In Vitro–InVivo Correlation
(IVIVC):A StrategicTool inDrug Development.J Bioequiv
Availab;2011.
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