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could prevent a successful correlation. Poor in vivo-in vitro correlations according to F.I.P. guidelines are characterized by |
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Differences in bioavailability data that are not observed in dissolution data, |
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Order of rates reversed in the two sets, |
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Significant differences in dissolution tests not observed in bioavailability data, and |
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Dissolution being inconsistent (accelerated or decelerated) with bioavailability data. |
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The most important and most frequently employed techniques for correlating in vivo and in vitro data are |
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Numerical deconvolution/convolution; |
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Statistical moment analysis; |
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Model dependent methods by |
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Loo-Riegelman, and |
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Wagner-Nelson; and |
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Regression type correlation of distinct single in vivo and in vitro parameters |
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B. What Parameters Should Be Considered in In Vivo-In Vitro Correlations? |
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The answer to this question is not easy. The gastrointestinal tract presents a complex and continuously changing environment for pH, enzyme secretions, motility, presence of other substances, absorption surfaces, absorption routes, and others. The manner in which these various factors influence drug bioavailability depends on the drug, the dosage form, the dosage regimen, the dose level, and patient or subject characteristics. |
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In vivo absorption may, or may not, be dissolution-rate limited. The drug, the dosage form, or both may have variable stability in the presence of gastrointestinal secretions and other gastrointestinal components. To these factors must be added other complicating factors, such as drug-drug interactions, food effects, age effects, and special patient populations. These factors may have an unpredictable effect on the rate and extent of drug absorption. In vivo availability is thus influenced by many factors in an environment that is far more complex, variable, and unpredictable than an in vitro test environment. |
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Some of the subtle factors that profoundly affect drug absorption, and yet many times are overlooked, should be considered. They include blood flow and drug permeability, food and fluid volume, antacids, drug metabolism and intestinal mucosa, metabolic activity of the intestinal microflora, and dissolution rate. These have been discussed in an earlier publication (Banakar and Makoid, 1992). |
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