IVIVC evaluation

The objective of IVIVC evaluation is to estimate the magnitude of the error in predicting the in vivo bioavailability results from in vitro dissolution data. This objective should guide the choice and interpretation of evaluation methods. Any appropriate approach related to this objective may be used for evaluation of predictability. 

With the exception of narrow therapeutic index drugs, the external predictability step in the IVIVC evaluation process may be omitted if the evaluation of internal predictability indicates acceptable % PE. However, when the evaluation of internal predictability is inconclusive, evaluation of external predictability is recommended. 

Since the IVIVC model is going to be used to predict the plasma concentrationtime profile, it is imperative to assess the predictive performance of the model via the assessement of the prediction error of the model. Depending on the intended application of the IVIVC and the therapeutic index of the drug, evaluation of the internal or external predictability may be warranted. Evaluation of internal predictability is based on the data that was used to develop the IVIVC. Evaluation of... 

At both the evaluation and the application level of a point-to-point IVIVC, in vitro dissolution data sets need to be treated and/or compared with each other. Appropriate methods vary with the data collection procedure and whether or not a model is to be fitted to the data. 

This chapter focuses primarily on the development and evaluation of IVIVC for ER oral products in accordance with the 1997 FDA Guidance. However, as the CPMP guidance provides almost identical information on these topics, the dis-... 

I-V Low Low Dissolution and uptake Case by case evaluation poor chance of IVIVC... 

Establishing in vitro in vivo correlation (IVIVC) for modified release dosage form provides a justification for waiving in vivo bioequivalence evaluation only for certain specified post approval changes. Since a correlation is dependent on the mechanism of drug release, it is not used in situations that could potentially alter its mechanism (16). 

A report from a 1990 ASCPT/DIA/APS/FDA-sponsored workshop entitled 7n vitro/In vivo Testing and Correlation for Oral Controlled/Modified Release Dosage Forms (1990) concluded that, while the science and technology may not always permit meaningful IVIVC, the development of an IVIVC was an important objective on a product-by-product basis. Procedures for development, evaluation, and application of an IVIVC were described. Validation of dissolution specifications by a bioequivalence study involving two batches of product with dissolution profiles at the upper and lower dissolution specifications was suggested. 

An rvrVC should be evaluated to demonstrate that predictability of in vivo performance of a drug product from its in vitro dissolution characteristics is maintained over a range of in vitro dissolution release rates and manufacturing changes. Since the objective of developing an IVIVC is to establish a predictive... 

An important concept is that the less data available for inihal IVIVC development and evaluation of predictability, the more additional data may be needed to define completely the IVIVC s predictability. Some combination of three or more formulations with different release rates is considered optimal. 

Methodology for the evaluation of IVIVC predictability is an active area of investigation and a variety of methods are possible and potentially acceptable. A correlation should predict in vivo performance accurately and consistently. Once this relationship has been achieved, in vitro dissolution can be used confidently as a surrogate for in vivo bioequivalence of ER drug products in the situations described below. 

Condition Dependent Dissolution. In all other instances where an IVIVC model is presented, results from a single formulation (one release rate) should be considered insufficient. To estimate internal and/or external predictability, evaluation of data from two or more formulations with different release rates is recommended. 

Estimation of Prediction Error Internally. The first aspect relates to evaluating how well the model describes the data used to define the IVIVC and is appropriate in all instances. 

Narrow Therapeutic Index Drugs. If an IVIVC model is to be used in estimating the in vivo performance of formulations of narrow therapeutic index drugs, the model s predictability should be tested further with a data set that differs from those data sets used to define the correlation. In other words, the external predictability of the correlation should be evaluated. 

If these criteria are not met, that is, if the internal predictability of the IVIVC is inconclusive, evaluation of external predictability of the IVIVC should be performed as a final determination of the ability of the IVIVC to be used as a surrogate for bioequivalence. 

The different points described in this section emphasize the numerous dissolution techniques that can be used to evaluate a new formulation in vitro. To ascertain IVIVC, the scientist must try numerous methods (apparatus, conditions, and media) in order to find the one, which gives the closest results to the in vivo dissolution/absorption curve. A dissolution test must reflect the in vivo behavior of the drug. A good dissolution technique is a method, which is simple to handle... 

If the IVIVC for a non-narrow therapeutic index drug was developed with formulations with three or more release rates, the evaluation of the internal predictability would be sufficient to determine its appropriateness. 

The most common approach to evaluating the predictability of an IVIVC is depicted in Figure 46.7. The procedure involves the conversion of the in vitro dissolution rate into in vivo absorption rate and then, by the use of convolution methods, a prediction of the plasma concentration-time prohle. This is represented as... 

For internal predictability, an average absolute prediction error of less than 10% for both AUC and Cn,ax establishes the predictive abiUty of the IVIVC. In addition, the percent error for each formulation should not exceed 15%. If the above criteria are not met, the IVIVC is declared inconclusive and in this case the evaluation of the external predictability of the IVIVC is required. 

For external predictability, the percent prediction error should be less than 10% to declare the IVIVC acceptable. A percent prediction error between 10% and 20% is deemed inconclusive, requiring the further evaluation with additional data sets. 

FIGURE 46.7 Most common approach in evaluating the predictabihty of an IVIVC—the conversion of in vitro dissolution rate into in vivo absorption rate and the prediction of plasma concentration-time profile by the use of deconvolution methods (see Section 46.5). 

The establishment of a predictive relationship between in vitro dissolution and the in vivo bioavailability of a modified release formulation is discussed. Establishing an rvrvC would decrease the number of studies required to approve and maintain a product on the drug market. A predictive level A correlation would enable the in vitro dissolution to become a surrogate for the in vivo performance of the drug product. This is one of the instances where regulatory decisions are made based on modeling and simulation data. The ability to describe both the in vitro and in vivo performance with well established mathematical models and the availability of different software that are able not only to fit the data but predict the resulting plasma concentration-time profiles should make the development, evaluation, and applications of IVIVC a routine endeavor in the development of modified release formulations. 

This evaluation may be performed either by use of the same data, as included in the establishment of an IVIVC (internal predictability), or by use of other data sets (external predictability). The criteria for concluding a level A IVIVC in a regulatory context requires, in the case of internal predictability, an average percentage PE of < 10 percent for Cmax and AUC, respectively, and the percentage PE for each formulation regarding these two bioavailability variables should not exceed 15 percent (FDA 1997a). 

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