Invitro invivo correlation

Invitro invivo correlation in dissolution data

1. IN VITRO – IN VIVO CORRELATION Presented by : M. Haritha M. Pharamcy 1 st Year 2018MPH40A018 1 UNDER THE GUIDANCE Prof. R. Nagaraju Institute of Pharmaceutical Technology Sri Padmavathi Mahila Visvavidyalayam ( Women's University) Tirupati Andhra Pradesh, India

2. CONTENTS : INTRODUCTION DEFINITION APPROACHES FOR DEVELOPING CORRELATION LEVELS OF IVIVC METHODS OF IVIVC APPLICATIONS OF IVIVC CONCLUSION REFERENCE S 2 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

3. IVIVC IN VITRO IN VIVO 3 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

4. INTRODUCTION: The therapeutic efficacy of a pharmaceutical formulation is governed by factors related to : Invitro Dissolution characteristics of the drug and its in vivo bioavailability. These inherent interdependency within the drug- patient bio system is the major concern that underlines the importance of in vitro in vivo correlation studies. 4 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

5. Invitro dissolution refers to the process of dissolution of drug from dosage form as measured in an invitro dissolution apparatus. In vivo dissolution refers to the process of dissolution of drug in the gastro intestinal tract. Correlation is the relationship between invitro dissolution rate and in vivo input(Absorption rate) are used in bioequivalence guidance. The need for such comparisons has been recognized since early 1960 s and the regulation on bioavailability and bioequivalence were issued by FDA in 1977. Wagner has stated that , “Future research in dissolution rate should be directed mainly towards establishing correlation of invitro data in vivo data.” 5 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

6. DEFINITION: In IVIVC “C” denotes “ Correlation”, which means the degree of relationship between two varibales . These term does not limit a relationship to only the linear type, but allows for nonlinear relationships as well. FDA has defined IVIVC as “A Predictive mathematical model describing relationship between invitro property of a dosage form and in vivo response”. Invitro properties are rate or extent of a drug released under a given set of conditions. Invivo properties are plasma drug concentration expressed in terms of C max , AUC. 6 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

7. OBJECTIVE: The main objective of developing and evaluating an IVIVC is to enable the dissolution test to serve as Surrogate(Alternate) for in vivo bioavailability studies in human beings. 7 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

8. BASIC APPROCHES: The basic approaches by which correlations between dissolution testing and bioavailabilty are : Predicting the mathematical model (Linear relationship) between invitro dissolution testing and existing bioavailibity data. Modifying, the dissolution methodology on the basis of existing bioavailability and clinical data . 8 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

9. NEED FOR IVIVC Theoretical worth while , but clinical approach is a poor tool for accurate measurement of bioavailability. Determination of drug level at the site of administration Urinary excretion of analysis of drug is meaningful for establishing IVIVC but complicated pharmacokinetic consideration. Thus , it is generally assumed that blood (Serum/Plasma) level measurements give a better assessment of bioavailability and bioequivalence. Decreased regulatory burdens . 9 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

10. SOME OF THE OFTEN USED QUANTITATIVE LINEAR IN VITRO- IN VIVO CORRELATIONS ARE: 1. Correlation based on plasma level data. 2. Correlation based on urinary excretion data. 3. Correlation based on pharmacological Response. 10 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

11. STATISTICAL MOMENTS THEORY : It can also be used to determine the relationships such as Mean dissolution time ( In vitro ) versus Mean residence time ( In vivo ). Though the examples of good correlations are many, there are instances when positive correlation is difficult or impossible. E g : Incase of corticosteroids , the systemic availability may not depend upon the dissolution characteristics of the drug. Several factors that limit such as correlation include dissolution methodology, physicochemical properties of the drug, physiological variables, like pre systemic metabolism. 11 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

12. LEVELS OF IVIVC 12 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

13. 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 of Deconvolution method. Estimation of the in vivo absorption profile using Wagner- Nelson or Loo-Riegelman. Comparision of fraction of drug absorbed( F a ) and fraction of drug dissolved(F d ) invitro to obtain a liner correlation. PURPOSE –DEFINES DIRECT RELATIONSHIP 13 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

14. Formulations showing Level A correlation require no additional human studies to change in manufacturing site, raw material supplier or minor formulation changes Most informative and very useful from a regulatory perspectives. 14 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

15. 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. 15 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

16. LEVEL B A predictive model for relationship between summary between summary parameters that characterize the in-vitro and in-vivo time course . It compares a) MDT vitro to MDT vivo, b) MDT vitro to MRT, In vitro Dissolution Rate Constant (kd) to Absorption Rate Constant (ka). Comparison using Statistical Moment Analysis Method. This type of correlation uses all of the invitro and invivo data. 16 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

17. This is of limited interest and least useful for regulatory purposes because more than one kind of plasma curve produces similar MRT. 17 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

18. LIMITATIONS Level B correlation is not unique, because MRT remains same, though the shape of invivo curves are different. Therefore it fails to justify the formulation modification . 18 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

19. LEVEL C CORRELATION : Predictive mathematical model which relates one dissolution time point (e.g .t 50% )to one pharmacokinetic parameter that characterizes in-vivo time course. (eg. C max ,T max ,T 1/2 or AUC) Level C correlations can be useful in the early stages of formulation development when formulations are being selected. Lowest correlation level. Does not reflect a complete shape of plasma concentration time curve. 19 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

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21. MULTIPLE LEVEL C CORRELATION : It relates one or more pharmacokinetic parameters to the present 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. 21 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

22. LEVEL D CORRELATION : It is not a formal correlation but it is a semi quantitative (quantitative analysis)and rank order correlation and is not considered useful for regulatory purposes. Serves as an aid in the development of a formulation or processing procedure. 22 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

23. LEVEL IN VITRO INVIVO A Dissolution curve Input (absorption) Curves B Statistical moments : Mean Dissolution Time(MDT) Statistical moments: Mean Residence Time (MRT),Mean Absorption Time (MAT),etc C Disintegration time , Time to have 10,50,90% dissolved, Dissolution rate, Dissolution efficiency. C max, Tmax , Ka to have 10,50,90 %absorbed , AUC ( total or Cumulative) 23 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

24. 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. 24 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

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26. IMPORTANCE OF IVIVC : To reduce the number of human studies. It serves as a surrogate of in vivo bioavailability. To set the dissolution specifications. To develop the drug delivery systems. To support biowaiver for bioequivalence studies. Research tool for Formulation Screening. 26 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

27. APPLICATONS OF IVIVC : 1. Application in drug delivery system 2. In early stages of drug delivery technology development. 3. Formulation assessment : Invitro dissolution . 4. Dissolution specifications. 5. Future bio waviers. 6. IVIVC Parenteral drug delivery. 27 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

28. 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 designs : Being in vitro model, it is natural to have certain limitations . The physics of tableting as well as nature of mechanical and hydrodynamic forces that operate during dissolution are not well understood. 28 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

29. CONCLUSION : IVIVC is a tool applied in various areas and stages of drug development to find a phase in the regulatory bodies around the world. 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. IVIVC can serve as surrogate for in vivo bioavailability and to support waviers also allows setting the dissolution specification methods . 29 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

30. REFERENCES : Shargel L, Andrew YU , Applied Biopharmaceutics and Pharmacokinetics . Brahmankar DM, Jaiswal SB, Biopharmaceutics and Pharmacokinetics. Subramanyam CVS , Biopharmaceutics and Pharmacokinetics . www.google.com. 30 Sri Padmavathi Mahila Visvavidyalayam ( Women's University ) Tirupati

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