BCS-based biowaivers : risks and opportunities

Bei peroral eingenommenen Arzneimitteln wird das Plasmakonzentrations-Zeit-Profil des aktiven Stoffes im Allgemeinen als Maß für die Wirksamkeit und Sicherheit des Arzneimittels angesehen. Bei Veränderungen an bestehenden Arzneimitteln oder der Entwicklung eines Generikums kann durch Bioäquivalenzstudien an gesunden Probanden untersucht werden, ob das Plasmakonzentrations-Zeit-Profil gleich bleibt. Auf eine solche Studie kann verzichtet werden (sog. Biowaiver), wenn ausreichend bewiesen ist, dass das Test- und das Referenzprodukt in vitro äquivalent sind. Die Möglichkeit für einen Biowaiver hängt von den Eigenschaften des aktives Stoffes und der Formulierung ab. Die vorliegende Doktorarbeit untersucht die internationalen (US, EU und WHO) regulatorischen Bedingungen für einen Biowaiver aus einer risikoorientierten Perspektive mit dem Ziel, neue Möglichkeiten für einen Biowaiver zu identifizieren. Offensichtlich sind die Bedingungen für einen Biowaiver weltweit verschieden. Unterschiedliche Definitionen der Löslichkeit eines Arzneistoffes können entscheidende Konsequenzen haben für die Daten die für den Nachweis der Bioäquivalenz nötig sind. Eine Harmonisierung der Kriterien durch die Zulassungsbehörden, akademische Welt und Industrie könnte die Anwendung des Biowaiveransatzes vereinfachen und die Zahl der klinischen Studien verringern. Das Verständnis der biopharmazeutischen Effekten von Hilfsstoffen könnte die Möglichkeiten für einen Biowaiver erweitern. Laktose wird zum Beispiel in sehr unterschiedlichen Mengen in vergleichbaren Tabletten und Kapseln mit Arzneistoffen aus unterschiedlichen Klassen des Biopharmaceutics Classification Systems (BCS) kombiniert. Daneben ist aus der Literatur bekannt, dass Laktose höchstens einen Effekt auf die Freisetzung des aktiven Stoffes hat und nicht auf andere Parameter. Daher könnte eine vergleichende In-vitro-Wirkstoff-Freisetzungsstudie ausreichend sein um eine Veränderung des Laktosegehaltes im zugelassenen Bereich zu unterstützen. Die Möglichkeiten der Anwendung von neuen Modellen für Biowaiver wurden anhand von Chitosan untersucht. Chitosan ist bekannt als ein potentieller Modulator der intestinalen Absorption. In einer klinischen Studie hatte Chitosan einen signifikant negativen Effekt auf auf die Maximalkonzentration (Cmax), den Zeitpunkt ihres Auftretens (tmax) und die Fläche unter der Kurve (AUC) von Acyclovir. Der Effekt der gleichen Chitosankonzentration wurde danach in einem Biozugänglichkeitmodell und in vier Permeationsmodellen untersucht. Auch wenn die Ergebnisse variabel waren, wurde in allen Permeationsmodellen bestätigt, dass Chitosan potentiell die intestinale Permeabilität beeinflussen kann. Ein Biowaiver auf der Basis des biopharmazeutischen Klassifikationssystems ist daher nicht gerechtfertigt bei einer Veränderung dieses Hilfsstoffes.Summary For orally administered products with systemic action, the plasma profile of the active pharmaceutical ingredient is generally considered as a measure of both efficacy and safety of the medicinal product. In case of changes to an existing product or development of a generic version, confirmation of equivalent plasma profiles is sought through a so-called bioequivalence study. Such an in vivo bioequivalence study in human volunteers may be waived if there is sufficient in vitro evidence of the equivalence of the test and reference products at issue. Biowaiver options depend on the characteristics of the API and the formulation. This thesis evaluates international (US, EU and WHO) regulatory conditions for biowaiving from a risk-based perspective with the aim to identify new biowaiver options. Regional differences in biowaiver conditions are obvious. Deviating definitions of the substance characteristic ‘solubility’ may have important consequences for the required evidence to show bioequivalence of a generic product. Harmonisation of the criteria as a common effort of authorities, academia and industry may facilitate application of the biowaiver approach and thus reduce the number of human studies. Understanding of the biopharmaceutic effects of excipients may extend biowaiver options. Lactose, for example, is used in highly variable quantities in similar tablets and capsules in combination with APIs from different BCS classes. In addition, an effect of lactose on other parameters than dissolution is not known from literature. Therefore, a comparative in vitro dissolution study is considered sufficient to support a change in lactose content if varied within the approved range. The biopharmaceutic effects of potential excipient chitosan on the absorption of acyclovir were explored both in humans and in several models. In a human study, chitosan showed a significant negative effect on Cmax, Tmax and AUC of acyclovir. The effect of the same chitosan on acyclovir was then tested in a bioaccessibility model as well as in four permeation models. The results showed potential intestinal permeability modulating characteristics of chitosan. A BCS-based biowaiver for a change in this potential excipient does thus not seem a viable option. Further studies are necessary to determine the suitability of the models for application as a tool for biowaiver purposes

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir.

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed

The effect of chitosan on the bioaccessibility and intestinal permeability of acyclovir

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed.status: publishe

In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing.publisher: Elsevier articletitle: In vivo methods for drug absorption – Comparative physiologies, model selection, correlations with in vitro methods (IVIVC), and applications for formulation/API/excipient characterization including food effects journaltitle: European Journal of Pharmaceutical Sciences articlelink: http://dx.doi.org/10.1016/j.ejps.2014.02.010 content_type: article copyright: Copyright © 2014 Elsevier B.V. All rights reserved.status: publishe