IN VITRO -IN VIVO CORRELATION (IVIVC)

PRESENTED BY, VINEETHA K DEPT. OF PHARMACEUTICS 1ST M. PHARM NGSMIPS

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

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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.

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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.

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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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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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APPROACHES FOR DEVELOPING 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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NEED FOR IVIVC 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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Some of the often used quantitative linear in 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.

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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.

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LEVELS OF IVIVC: 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.

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LEVEL A CORRELATION:• 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

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• 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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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.

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LEVEL B CORRELATION: 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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LEVEL B CORRELATION:

Figure 2: Correlation of mean in vitro dissolution time(MDT) and mean absorption time(MAT).

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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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LEVEL C CORRELATION: 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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LEVEL C CORRELATION:

Figure 3: correlation between mean dissolution time and AUC of plasma drug time curve of four formulations.

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MULTIPLE LEVEL C CORRELATION:• 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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LEVEL D CORRELATION: 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.

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LEVEL IN VITRO IN VIVOA 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 absorptionB: correlation based on statistical moments, e.g., in vitro MDT vs. in vivo MRT or MATC: 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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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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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)

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IMPORTANCE OF

IVIVC

To reduce the

number of human studies

As a surrogateof in vivobioavailab

ility

To set the dissolution specificatio

ns

Development 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

relationship

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APPLICATION OF AN IVIVC: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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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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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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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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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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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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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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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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REFERENCE:

1.Shargel L, Andrew YU. Applied Biopharmaceutics and Pharmacokinetics. 2nd Edn. Singapore: The McGraw-Hill Companies; 2012.380-386p.2. Subrahmanyam CVS. Biopharmaceutics and Pharmacokinetics- concepts and application. 1st Edn. Delhi: Vallabh Prakashan; 2010. 164p.3.Brahmankar DM, Jaiswal SB. Biopharmaceutics and Pharmacokinetics- A treatise. 2nd Edn. Delhi: Vallabh Prakashan; 2009. 332p.4. Sakore S, Chakraborty B. In Vitro–In Vivo Correlation (IVIVC): A Strategic Tool in Drug Development. J Bioequiv Availab ;2011 .