Masterarbeit

Comparison of In Vitro Drug Release and In Vivo Data (Bioavailability) of Prolonged Release Oral Dosage Forms - Introduction to Basic Techniques ***

Eva Eisenhut (2002)

The scientific interest in establishing a relationship between an in vitro characteristic of a dosage form and its in vivo performance dates back to the development of the disintegration test for tablets and capsules (adopted in USP XIV in 1950) though without quantitative work at that time. The emerging dissolution testing technology (first dissolution requirements added to USP monographs in 1970) provided the basis for quantitative attempts. Today in vitro drug release from a dosage form is used as the physicochemical component in the comparison necessary to elaborate the correlation. While the concept is not restricted to pharmacokinetic parameters following administration of the medicinal product, they are most commonly employed as the biological counterpart in this comparison. Prolonged release dosage forms have been a special focus of research. The prognosis for a meaningful relationship is at the same time promising on account of their design principle: Drug release is intended to be the rate determining step for absorption of the drug substance into the systemic circulation. Oral prolonged release dosage forms are first line candidates for a comparison with well established in vitro release test methodologies. Although a meaningful correlation will not be feasible in every case, regulatory guidelines encourage applicants for marketing authorisations for medicinal products in the US and the EU to investigate the possibilities to qualify the in vitro drug release test of prolonged release dosage forms as a biorelevant tool for performance prediction during pharmaceutical development, quality control throughout stability tests and routine production as well as a surrogate for bioequivalence testing to allow the evaluation of certain pre- and postapproval changes without additional studies in man. By international consensus correlation types are categorised into levels A, B and C with the subclass multi-level C: Level A correlations associate in vitro and in vivo release profiles point to point, level B correlations connect pairs of curve parameters summarizing time courses, level C correlations formulate a mathematical relationship between couples of single pharmacokinetic parameters with single parameters taken from the dissolution curve. Recommendations on a suitable data basis of in vitro and in vivo studies as well as on comparison techniques (interpretation of pharmacokinetic data by linear systems analysis, compartmental modelling, statistical moment analysis) are given in the guidelines. The quality of the established correlation is determined by the ability to predict pharmacokinetics through in vitro release data. Level B and C correlations do not reflect plasma level profiles and are therefore less useful for regulatory purposes, level A correlations should be aimed at from a regulatory point of view to avail of the advantages of an in vitro release test qualified as a surrogate for pharmacokinetic studies. The establishment of an in vitro/in vivo correlation for a prolonged release oral dosage form is an active area of pharmaceutical development. The correlation provides a sound basis for discussion with authorities during the initial approval procedure of the medicinal product as well as when proposing scale-up and postapproval changes, the considerable development effort is an investment into the understanding of the in vivo release of the dosage form and some manufacturing flexibility within the limits of the formulation design of release mechanism/release controlling excipients.

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