In Vitro-In-Vivo Correlations(IVIVC)

At the end of this presentation you will be able to: Understand basic concepts of IVIVC Understand the application of IVIVCs Understand how to establish correlation Use the data appropriately for correlation

Know the levels of IVIVCs used

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Introduction

Definition of IVIVCs:

A predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response. (FDA ) The establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and a physicochemical property of the same dosage form. (USP)
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Intro
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. Typically, the parameter derived from the biological property is AUC or Cmax, while the physicochemical property is the in vitro dissolution profile. The IVIVC for a formulation is a mathematical relationship between an in vitro property of the formulation and its in vivo act.
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Intro
Correlations between in vitro and in vivo data (IVIVC) are often used during pharmaceutical development in order to reduce development time and optimize the formulation. A good correlation is a tool for predicting in vivo results based on in vitro data. Correlation can generally be expected when drug release from the formulation is the step controlling of the subsequent absorption kinetics.

J-M. Cardot1, E. Beyssac, and M.Alric

intro
Based on regulatory guidelines, the in vitro profiles are regarded acceptable for an IVIVC: (i) When the dissolution rate is a mean of twelve individual determinations and (ii) the coefficient of variation at each sampling point is less than 10%; however the initial release data may exhibit a larger variability The in vitro dissolution testing is used to accept or reject formulation. The acceptable formulations are considered bioequivalent in terms of in vivo performance and vice versa.
Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012

Intro
The IVIVC cannot be used across the products, especially drug product with different release mechanisms. A theoretical basis has been developed for developing correlation between in vitro dissolution and in vivo bioavailability depending on the solubility and permeability of drug. BCS is a predictive approach for developing correlation between physicochemical characteristics of a drug formulation and in vivo bioavailability.
www.locumusa.com (IJGD) Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012

Roles of IVIVCs
IVIVC plays an important role in product development in that it: Serves as a surrogate of in vivo and assists in supporting biowaivers Supports and validates the use of dissolution methods and specifications The dissolution testing method in IVIVC development and validation is to serve as a surrogate measure of the rate and extent of oral absorption. Assists in quality control during manufacturing and selecting appropriate formulations
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Levels of IVIVCs
The five levels of IVIVC correlations as narrated in FDA guidelines (U.S. Department of Health and Human Services, 1997; Khan et al., 2010) are: 1. Level A correlation 2. Level B correlation 3. Level C correlation 4. Level D correlation 5. Multiple level C correlation

Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012

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Levels of
Level A correlation: A higher level of correlation. A correlation of this type is generally linear Elaborates point to point relationship between in vitro dissolution and in vivo absorption rate of drug from the formulation. Level B correlation: The mean in vitro dissolution time is compared either to the mean residence time(MRT) or to the mean in vivo dissolution time(MDT). Does not uniquely reflect the actual in vivo plasma level curve,because a number of different in vivo curves will produce similar mean residence time values.
Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012
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Levels of
Level C A weak single point relationship having no reflection of dissolution or plasma profile. Useful in the early stages of formulation development when pilot formulations are being selected. compares the amount of drug dissolved at one dissolution time-point to one pharmacokinetic parameter like t60% to AUC. Does not reflect the complete shape of the plasma concentration-time curve, which is the critical factor that defines the performance of ER produc
Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012/AJPP
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Levels of
Level D correlation helping in the development of a formulation. It is a rank order analysis which is not considered as a formal correlation (U.S. Department of Health and Human Services, 1997). Multiple level C Relate several in vivo parameters to in vitro parameters related to drug release , at several time points of the dissolution profile. Multiple level C correlation can be as useful as level A correlations.

Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012 /AJPP

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How to develop IVIVC and validate it ?

FDA has introduced the guidelines, how to develop IVIVC and validate it by internal and external approaches (Khan et al., 2010). Internal validation elaborates the predictability of data that has been employed in the model development and is recommended for all IVIVC analysis (U.S. Department of Health and Human Services, 1997). External validation depends on how efficiently the IVIVC predicts additional data sets. This predictability is considered better than the internal one. To develop IVIVC, commonly three formulations with different release rates are used; fast, medium and slow release formulations
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IVIVC development and its analysis

For analysis and development of IVIVCs obtention and analysis of in vitro and in vivo data is needed. A reliable in vitro dissolution test for a drug substance is necessary for the development of IVIVC. After development of a reasonable dissolution medium, the in vitro dissolution testing is performed for suitable time period on the formulations selected. The dissolution samples are analyzed spectrophotometrically or chromatographically, to find out the amount of drug released. Consequently, the drug release versus time profiles are obtained for correlating with in vivo data.

Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012

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IVIVCs development and

To establish IVIVC, in vivo absorption data is also required which means that pharmacokinetic and bioavailability study is also to be done. PK study involves the study of the influence of body on the drug, that is, ADME. Where as the bioavailability is commonly assessed by evaluating AUC, Cmax and tmax

Murtaza G. et al vol.6(4),pp.257-263,29 janua,2012

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IVIVCs development and

The bio-analysis of collected blood samples is conducted using validated analytical methods. The plasma drug concentration data is plotted against time points and This curve is used to calculate pharmacokinetic parameters such as AUC, AUMC, Cmax, Tmax and Ke (elimination rate constant) using an appropriate pharmacokinetic model through manual calculations or suitable software .

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IVIVCs development and

The association between the in vitro and in vivo data is stated mathematically by a linear or nonlinear correlation. But, the plasma drug concentration data cannot be related directly to the obtained in vitro release data. They are needed to be converted first to the fundamental in vivo release data using pharmacokinetic compartment model analysis or linear system analysis. Level A IVIVC correlates the entire in vitro and in vivo profiles (Rasool et al., 2010). In order to develop level A correlation, the fraction of drug absorbed (Fa) for a formulation is plotted against its fraction of drug dissolved (Fd), where Fa and Fd are plotted along x-axis and y-axis, respectively.
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IVIVCs development and

This curve provides basic information of the relationship between Fa and Fd, either it is linear or non-linear. Finally the regression analysis is performed for each curve to evaluate strength of correlation. The correlation is considered as efficient as the value of determination coefficient is closer to 1 (U.S. DHHS, 1997; WMAD Helsinki, 2008; Ahmad et al., 2008; Aamir et al., 2010). The predictability of the correlation is analyzed by calculating its prediction error (%). The deviation between prediction and observation is assessed either with internal validation or with external validation .
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IVIVCs development and

According to FDA guidelines, the correlation is considered predictive if mean prediction error across formulations is less than 10% for AUC and Cmax and the prediction error (%) for any formulation is less than 15% for AUC and Cmax (U.S. Department of Health and Human Services, 1997). Level B correlation is developed between MDT and MRT of a formulation. The MDT and MRT are plotted along x-axis and y-axis, respectively. The regression analysis is performed for this curve also (Ahmad et al., 2008). Level C correlation, a single point correlation, can be established by drawing a curve between t50% and pharmacokinetic parameter are plotted along x-axis and y-axis, respectively following regression analysis (Ahmad et al., 2008).

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Reference

Murtaza G. et al Vol. 6(4), pp. 257-263, 29 January, 2012 African Journal of Pharmacy and Pharmacology

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