jignesh patel,ivivc

PAPER 411/4 patel Jignesh.P.Patel M.PHARM-I

A seminar on Factor affecting IVIVC

Guided by: Presented by: Dr.Manish.P.Patel Patel Jignesh.P Head of Department M.pharm-1sem Department of pharmaceutics M.pharm, Nootan Pharmacy college Visnagar.

1/37


Area under discussion…INTRODUCTIONWHAT IS IVIVC?WHY TO GO FOR IVIVC?FACTORS IN DEVELOPMENT OF A PREDICTABLE IVIVCFEW DEFINITIONSLEVELS OF CORRELATION TYPES OF CORRELATIONMETHODS OF CORRELATIONSTAGES OF IVIVC MODEL DEVELOPMENT APPLICATIONS OF IVIVC IN DRUG DELIVERYWHATS IN STORE FOR THE FUTURE?STUDY QUESTIONSREFERENCES

2/37


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.

3/37


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.”

4/37


WHAT IS IVIVC???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.

5/37


WHY TO GO 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.

6/37


To explore the relationship

To assist quality control

for certain SUPAC.

Research tool for

Formulation Screening

To support biowaivers

for bioequivalence

testing

Development of drug delivery

systems.

To set the dissolution

specifications

As a surrogateof in vivo

bioavailability

To reduce the number of

human studies

IMPORTANCE OF

IVIVC

7/37


Establishing in vitro-in vivo correlation

Pharmacological correlations based on clinical observations.

Semi quantitative correlations based on the drug blood levels or urinary excretion data.

Quantitative correlations arising from absorption kinetics and calculation of in vivo dissolution rate and absorption rate constants.

8/37


Factors affecting development of a predictable IVIVC

DISSOLUTION METHOD

PYSICOCHEMICAL

METHOD

COMPOSITION

COMPLEXITY

9/37


Mean Residence Time: MRT = AUMC / AUC where, AUMC = Area under first moment Curve

(Concentration*time Vs time) AUC = Area under zero moment curve

(Concentration Vs time)

Mean Absorption Time: MAT = MRT oral – MRT i.v.

Mean In-vivo Dissolution Time: MDT solid = MRT solid – MRT solution

Percent Prediction Error: % PE = [(Observed value – Predicted value) / Observed value] x 100

FEW DEFINITIONS

10/37


LEVELS OF CORRELATION• There are four levels of IVIVC that have

been described in the FDA guidance, which include

Level A

Level B

Level C

Multiple C

11/37


Point-to-Point relationshipUsually Correlations are linear, and no formal guidance on the non-linear IVIVC.The data treatment involves a two stage Deconvolution Method.

1. Estimation of the in vivo absorption profile using Wagner-Nelson or Loo-Riegelman method

2. Comparison of fraction of drug absorbed (Fa) and fraction of drug dissolved (Fd) in-vitro to obtain a linear correlation.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.

LEVEL A CORRELATION

12/37


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.

Level B Correlation

13/37


Mathematical model of relationship between the amount of drug dissolved in-vitro at a particular time and a summary 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.

Level C Correlation

14/37


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.

• If a multiple Level C correlation is possible, then a Level A correlation is also likely and is preferred.

Level In vitro In vivo

A Dissolution curve Input (absorption) curves

B Statistical Moment: MDT

Statistical Moment: MRT, MAT

C Disintegration time, Time to have 10, 50, 90% Dissolved, Dissolution rate, Dissolution efficiency

Cmax, Tmax, Ka, Time to have 10, 50, 90% absorbed, AUC

15/37


Types of correlationQuantitative correlation: In vivo parameter-y, in vitro-x. y= mx +cPearson product moment correlation coefficient, quantify strength of relationship between x & y. r (-1 to +1)

Rank order correlation: (Spearman rank correlation, rs) Values of the two variables are ranked in ascending or descending order. Rank order correlations are qualitative and are not considered useful for regulatory purposes.

Correlation (r) between variables Linear relationship

+1 Perfect Positive

-1 Perfect Negative

0 No Linear Relationship

16/37


Correlation Methods

SIMPLE POINT TYPE

COMPARISON OF

PROFILES

DIRECT DIFFERENTIAL

EQUATION-BASED IVIVC

17/37


In vitro data In vivo data

1. Percent drug dissolution profile

o Percent drug dissolved at time t,o Time taken for maximum amount

of drug to dissolve. o Total amt. of drug dissolved.o Time for a certain percentage of

drug to dissolve such as t30% t50% t90%

1. Plasma conc. time profile

o Plasma concentration at time t,o Cmax,o tmax,o AUCo

t AUCo∞

o t30%, t50%, t90%

2. Kinetic parameterso Dissolution rate constanto Dissolution half life

2. Pharmacokinetic parameterso Absorption & elimination rate

constant & half life

3. Percent drug dissolved time profile

o Percent drug dissolved at time t

3. Percent drug absorbed time profile

4. Statistical moment analysiso MDT

4. Statistical moment analysiso MRT, MAT

18/37


MODEL VALIDATION

STAGES OF IVIVC MODEL

MODEL DEVELOPMENT

19/37


Model DevelopmentThe principles of IVIVC model development have been successfully applied to oral dosage forms.

However, the rules for developing and validating IVIVC models for novel and non-oral dosage forms/delivery systems (micro spheres, implants, liposomes, etc) are still unclear today.

For orally administered drugs, IVIVC is expected for highly permeable drugs or drugs under dissolution rate-limiting conditions, which is supported by BCS.

For extended-release formulations following oral administration, modified BCS containing the three classes (high aqueous solubility, low aqueous solubility, and variable solubility) is proposed.

20/37


CLASS

SOLUBILITY

PERMEABILITY IVIVC EXPECTATION

I High High IVIVC: if dissolution rate is slower than gastric emptying rate.Otherwise limited or no correlation required

II Low High IVIVC is expected if in-vitro dissolution rate is similar to in-vivo dissolution rate, unless dose is very high.

III High Low Absorption/Permeability is rate determining and limited or no correlation with dissolution rate.

IV Low Low Limited or no IVIVC expected.

21/37


The most basic IVIVC models are expressed as a simple linear equation (Equation 1) between the in vivo drug absorbed and in vitro drug dissolved (released).

In this equation, m is the slope of the relationship, and C is the intercept. Ideally, m=1 and C=0, indicating a linear relationship.However, depending on the nature of the modified-release system, some data are better fitted using nonlinear models, such as Sigmoid, Higuchi, or Hixson-Crowell.

22/37


However, for dosage forms with complicated mechanisms of release (longer duration), in vitro release may not be in the same time scale as the in vivo release.

Thus, in order to model such data, it is necessary to incorporate time-shifting and time-scaling parameters within the model.

This kind of data is routinely encountered in the development of sustained-release dosage forms.

In vivo release rate (X’vivo) can also be expressed as a function of in vitro release rate (X’rel,vitro) with empirically selected parameters (a, b), as shown in Eqn 2.

23/37


Determining the fraction of dose absorbed

Model Dependent methods• Wagner Nelson Equation• Loo-Riegelman Method

Model Independent methods• Deconvolution

24/37


Model Validation

[1] Internal Validation(using data from the formulations used to build the model)

Internal validation serves the purpose of providing basis for the acceptability of the model.

[2] External Validation(using data obtained from a different (new) formulation)

External validation is superior and affords greater “confidence” in the model.

25/37


Internal Validation[1] Using the IVIVC model, for each formulation, the

relevant exposure parameters (Cmax and AUC) are predicted and compared to the observed values.

Prediction Error (%PE) = ( Cmax observed – Cmax predicted) * 100 Cmax observed

= ( AUC observed – AUC predicted ) * 100 AUC observed

[2] The criteria set in the FDA guidance on IVIVC are: For Cmax and AUC, the mean absolute % PE should not exceed 10%, and the prediction error for individual formulations should not exceed 15%.

26/37


External Validation[1] For a new formulation the relevant exposure

parameters are predicted using its in vitro dissolution profile and the IVIVC model and are compared to the observed parameters.

[2] For Cmax and AUC, the % PE for the external validation formulation should not exceed 10%. A prediction error of 10% to 20% indicates inconclusive predictability and illustrates the need for further study using additional data sets.

[3] For drugs with narrow therapeutic index, external validation is required despite acceptable internal validation, whereas internal validation is usually sufficient with non-narrow therapeutic index drugs. 27/37


IVIVC – PARENTERAL DRUG DELIVERY

DISSOLUTION SPECIFICATIONS

FORMULATION ASSESSMENT

EARLY STAGES OF DRUG DELIVERY

TECHNOLOGY DEVELOPMENT

FUTURE BIOWAIVERS

APPLICATIONS OF IVIVC

IN DRUG DELIVERY

Potent Drugs & Chronic Therapy

Limited volume

Burst Release

28/37


CAUSES OF FAILURE OF PARENTERAL IVIVC

a) Burst Release: Unpredictable and Unavoidable.

b) Potent Drugs & Chronic Therapy: Complex design of parenteral drug delivery systems.

c) Limited volume of tissue fluids & Area of absorption at the site of administration, unlike following the oral route of administration.The drug conc. should be monitored in the in vivo tissue fluids at the site of administration by techniques such as microdialysis.

29/37


WHATS IN STORE FOR THE FUTURE>>>

IVIVR (In vitro-in vivo relationship) • One possible substitution for IVIVC is IVIVR, with

"R" denoting "relationship." • Hence, IVIVR need not be limited to straight-line

relationships, which generally fails for IR products. • This IVIVR analysis has been applied to several

formulations of metoprolol, piroxicam, and ranitidine.

• This indicated that one intent of IVIVR should be to learn about the relative contribution of dissolution to a product's overall absorption kinetics.

30/37


DISSOLUTION SIMULATORSIntroduced to enhance the capability of in vitro

dissolutionas a predictor of the in vivo behavior of dosage forms.

But, highly complex and expensive apparatus.

a) Groning’s Model b) Sartorius Dissolution simulator c) Sartorius Membrane Filter Solubility

Simulatord) Sartorius Membrane Filter Absorption

Simulator

31/37


GRONINGS MODEL

GLASS BEADS

SINTERED GLASS FILTER

AXIS OF ROTATION

SINTERED GLASS FILTER

POROUS PLASTIC

The dosage form disintegrates in the gastric part of the model and some of the drug particles are continuously pumped into the intestinal part. Cells are rotated by a slow speed electric motor. Good IVIVC for all Nitrofurantoin tablets & capsules tested.

32/37


CONCLUSION

Dissolution promotes good bioavailability but does not assure it.

Meaningful IVIVC is possible only when dissolution rate dominates membrane transport and transit rate, thus limiting the rate and/or extent of absorption.

In the era of tight budgets and increasing costs of drug development, the most critical application of IVIVC with respect to cost savings is the biowaiver, the avoidance of expensive clinical trials.

While the principles of IVIVC have been mostly applied to oral products, there exists a need to develop methodologies and standards for non-oral delivery systems.

33/37


STUDY QUESTIONSWhat do you mean by IVIVC? Add a brief note on its importance.Discuss different levels of correlation given by FDA?Add a note on stages of IVIVC Model development?Describe in brief application of IVIVC?Add a note on future directions of IVIVC?Write short note on– IVIVR– Dissolution simulators– Parenteral IVIVC– Causes of failure of Parenteral IVIVC

34/37


REFERENCESIVIVC: An Important Tool in the Development of Drug Delivery Systems; Gangadhar Sunkara, PhD, and Dakshina M. Chilukuri, PhD. http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=144

Dissolution, Bioavailability and Bioequivalence by Hamed M. Abdou, Mack Publishing House.

Guidance for Industry; Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations. www.fda.gov/cder/guidance/index.htm

35/37

http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=144

http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=144

http://www.fda.gov/cder/guidance/index.htm


IVIVC Vs IVIVR; James E. Polli, Ph.D. http://www.dissolutiontech.com/DTresour/800Articles/800_art1.html

IVIVC: Methods and Applications in Modified-Release Product Development; Harald Rettig and Jana Mysicka. Dissolution Technologies | FEBRUARY 2008.

Journal Metadata Search: Pharmaceutical Press - Journal of Pharmacy and Pharmacology 55(4); 495 (2003)

In Vitro–In Vivo Correlation: Importance of Dissolution in IVIVC; J-M. Cardot, E. Beyssac, and M.Alric. Dissolution Technologies | FEBRUARY 2007

36/37

http://www.dissolutiontech.com/DTresour/800Articles/800_art1.html

http://www.dissolutiontech.com/DTresour/800Articles/800_art1.html


“THERE IS ALWAYS SOMETHING MORE THAN YOU CAN DO”

37/37

jignesh patel,ivivc

Education

levels of ivivc

predictable ivivc

nonlinear ivivc

correlation studies

linear correlation

level b correlation

dissolution time

type of correlation