Dissolution – Bioequivalence Non‐Correlations

Abstract

The World Health Organization (WHO) rules (1996) recommend in chapter 3 ''Technical data for regulatory assessment'' that information for marketing authorization should contain among others in-documentation, equivalence data (comparative bioavailability, pharmacodynamic or clinical studies), and comparative in vitro dissolution tests. European rules concerning evaluation of bioavailability and bioequivalence (CPMP/EWP/QWP/1401/98) specify in chapter 5.2: ''Dissolution studies are always necessary and consequently required. In vitro dissolution testing forms a part of the assessment of a bioequivalence waiver''. The consequence is that over the last years all over Europe dissolution studies were connected to bioequivalence studies and the natural tendency was to correlate the results obtained in the pair studies in order to obtain models allowing dissolution results as predictor for in vivo results.Let us consider only as a mnemotechnique, the living body as a ''mathematical operator'' which transforms parameters characterizing dissolution curves in pharmacokinetic parameters associated to plasma levels curves. y (dissolution) Ω pharmacokineticsIf we consider the two spaces as ordered metric spaces, a natural question is that the operator preserves the distances and order. For example, if we compare a tested drug T with a reference one R, we would be interested to know ifLess formally speaking we are interested to know if in vitro similarity implies bioequivalence and if a better dissolution implies a better bioavailablity. It is clear that the response depends on the active substance and physiopatological parameters but also on the particular metrics choiced for characterizing in vitro and in vivo curves as well as distances between its. The response is not so simple, first of all since due to the complexity of the phenomena studied, both metrics and order in vitro and in vivo are not well defined. The great number of dissolution and bioequivalence metrics (Enachescu et al. 2003) show that the problem is yet to be solved.In vitro dissolution tests. Dissolution tests were performed using the method indicated by USP or according to the specifications provided by the producers. As metrics of dissolution were considered the factors f 1 and f 2 .Clinical trials. Each study was performed on healthy volunteers. Experiments were of the standard type: cross-over, with two periods and two sequences.Analytical methods. Plasma levels of the drugs were evaluated using validated liquid chromatographic methods, with UV or mass spectometry detection.In judging the results it should be kept in mind that that in so-called in vitro/in vivo correlations, we practically jump over one step -in vivo dissolution, which is by far more variable and more complex than the in vitro dissolution. Since in vitro dissolution conditions are often far from the in vivo conditions, we have non-correlation between the two dissolutions.Similar dissolution and non-bioequivalence. This is the case for many acidic or basic drugs. Most representative is ...

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