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e.g. peak time in vivo with in vitro dissolution, T50%. As would be expected, the first applications of computers to this kind of data were essentially not to change the end result but simply to get there faster. Recently, suggestions regarding in vivo-in vitro correlation have been made which depart from such classical analytical procedures. These suggestions begin to utilize the power of the computer for the very first time. The premise is that in order for data from one set to be comparable to data from another the two sets must be similar. The in-vitro dissolution profile of a tablet can be expressed in two forms as can the in vivo absorption data. Both may be expressed in cumulative-amount-versus-time or rate-versus-time terms. In vitro cumulative amount released and in vivo cumulative amount absorbed is a comparable pair as is in-vitro rate of release and in vivo rate of absorption while comparisons of rate with cumulative amount are not. Thus only similar parameters derived from comparable pairs would be allowed and the arbitrary combinations of parameters from dissimilar pairs would not. These are the current guidelines when submitting this type of data for regulatory approval. |
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It is well accepted that the movement of the individual drug molecules through the body compartment is governed by probability. The time course of drug concentrations in plasma can usually be regarded as a statistical distribution curve. The acceptance of a drug molecule in a biological fluid such as blood, i.e., absorption, can be conceived in terms of the biological system responding to the incoming drug molecule. Thus, the drug concentration-time profile can be viewed as system response-time profile. Similar argument can be presented in favor of in vitro dissolution test system and the drug dissolving (being accepted) in the dissolution medium. Thus both in vitro dissolution-time profile and blood/plasma-time profile as well as urinary excretion-time profile can be expressed as system response as a function of time (Fig. 30). Both in vitro and in vivo system response as a function of time are analogous and can be thus compared and correlated. |
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A logical extension of the concept of correlating analogous parameters is not to compare only similar parameters derived from similar data representations, but to compare those entire data sets directly. This would be done by |
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1. Fitting the data from similar pairs to equations through nonlinear regression analysis (MINSQ), |
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2. Using the ability of MINSQ to find intrinsic variables, to determine the times for the fractional system response, and |
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3. Plotting the correlated fractional system response times in vivo as a function of in vitro. |
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The plot of corresponding fractional system response times would yield a function that correlated the similar paired data sets. Stepping through this |
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