European Journal of Pharmaceutical Sciences 57 (2014) 292–299
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Review
Oral biopharmaceutics tools – Time for a new initiative – An introduction to the IMI project OrBiTo H. Lennernäs a, L. Aarons b, P. Augustijns c, S. Beato d, M. Bolger e, K. Box f, M. Brewster g, J. Butler h, J. Dressman i, R. Holm j, K. Julia Frank k, R. Kendall l, P. Langguth m, J. Sydor n, A. Lindahl o, M. McAllister p, U. Muenster q, A. Müllertz r, K. Ojala s, X. Pepin t, C. Reppas u, A. Rostami-Hodjegan v, M. Verwei w, W. Weitschies x, C. Wilson y, C. Karlsson z, B. Abrahamsson z,⇑ a
Uppsala University, Sweden University of Manchester, United Kingdom c Katholische University of Leuven, Belgium d Novartis, Switzerland e Simulations Plus, United States f Sirius Analytical, United Kingdom g Johnson & Johnson, Belgium h GSK, United Kingdom i Goethe University Frankfurt am Main, Germany j H. Lundbeck A/S, Denmark k Boehringer-Ingelheim, Germany l Merck, United Kingdom m Johannes Gutenberg University of Mainz, Germany n AbbVie, Germany o Medical Products Agency, Sweden p Pfizer, United Kingdom q Bayer Pharma AG, Germany r University of Copenhagen, Denmark s Orion Pharma, Finland t Sanofi-Aventis, France u National and Kapodistrian University of Athens, Greece v Simcyp Ltd/University of Manchester, United Kingdom w TNO, Netherlands x University of Greifswald, Germany y University of Strathclyde, United Kingdom z AstraZeneca R&D, Sweden b
a r t i c l e
i n f o
Article history: Received 19 June 2013 Received in revised form 22 October 2013 Accepted 24 October 2013 Available online 1 November 2013 Keywords: BCS PBPK IVIVC Dissolution Drug absorption Permeability
a b s t r a c t OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo
⇑ Corresponding author. Address: AstraZeneca R&D, S-43183 Mölndal, Sweden. E-mail address: [email protected] (B. Abrahamsson). 0928-0987/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejps.2013.10.012
293
H. Lennernäs et al. / European Journal of Pharmaceutical Sciences 57 (2014) 292–299
are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes. Ó 2013 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intestinal absorption – definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ‘Biopharmaceutical aspects in oral pharmaceutical formulation development’ . Current status of predictive biopharmaceutics tools . . . . . . . . . . . . . . . . . . . . . . The novel IMI project: OrBiTo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The Innovative Medicines Initiative (IMI) (http://www.imi.europa.eu/) is Europe’s largest public–private initiative in the life science sector between the European Union (EU) and the European pharmaceutical industry association (EFPIA). The aim is to speed up the development of better and safer medicines for patients and build networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. OrBiTo is a key initiative within IMI, designed to streamline and optimize the development of orally administered drug products with a strong focus to develop novel experimental and theoretical models to increase our knowledge of biopharmaceutical factors and their interplay with the dynamic gastrointestinal (GI) physiology (http://www.orbitoproject.eu, http://www.imi.europa.eu/content/ orbito). The project started October 1 2012 and will continue for five years and expected to start report novel findings during its second year. The OrBiTo project will address key gaps in our knowledge of GI drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through prospective studies to define new methodologies and to refine existing tools. Extensive validation of novel and existing tools will be performed using historical datasets from industry partners. A combination of high quality in vitro and in silico characterizations of active pharmaceutical ingredient (API) and formulations will be integrated into physiologically based in silico models capturing the full complexity of GI drug absorption. Thus, the OrBiTo project is expected to ‘‘change the game’’ in industrial product development from an essentially empirical approach (‘‘trial-and-error’’) to a more rational model-based approach. Scientific advances in the biopharmaceutical field will provide a step change in our ability to predict product in vivo performance in patients that will strongly impact the pharmaceutical development in a positive way. It may also provide the basis for revised regulatory guidelines in the context of Quality by Design (QbD) by providing reliable biopharmaceutics links between the API and its formulation on the one hand, and the patient and therapeutic goal on the other hand enabling more clinically relevant development targets and quality specifications. In order to achieve all of these goals, four separate work packages (WP1–4) have been created to develop suitable tools for characterizing the API, designing and characterizing the formulation, understanding the conditions in the GI tract better and optimizing the absorption aspects of physiologically based pharmacokinetic (PBPK) models. The objective of this overview is to describe the scope and objectives of the OrBiTo project. In the subsequent review articles
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in this special issue of European Journal of Pharmaceutical Sciences (EJPS), the status and gaps regarding in vivo predictive biopharmaceutics tools and the associated underlying science are addressed in more detail. 2. Intestinal absorption – definition Oral administration of pharmaceutical products is the preferred route for the majority of medical treatments. It is feasible and useful to evaluate the performance of orally administered drugs and dosage forms in the GI tract by analyzing the plasma drug exposure-time profile. The oral bioavailability (F) is one of the most useful pharmacokinetic (PK) parameters in this context and F is strongly related to the pharmacological effect and safety for systemically acting drug products. F is affected by a number of processes, discussed below. F is the result of three general processes: fraction dose absorbed across the apical cell membrane into the cellular space of the enterocyte, described as fa, intestinal first-pass metabolism (EG) and hepatic first-pass metabolism (EH) (Eq. (1)) (Rowland and Tozer, 1995).
F ¼ fa ð1 EG Þ ð1 EH Þ
ð1Þ
A schematic overview of most relevant processes involved is also provided in Fig. 1. The fraction of the dose absorbed (fa) is affected by various factors which influence drug release, dissolution, luminal degradation/complexation and intestinal wall permeability. In general, these factors can be grouped into three categories: (i) physico-chemical factors of the drug molecule itself, (ii) pharmaceutical factors such as design of formulations, including choice of excipients and the physical/solid state form of the drug in the final product, and (iii) physiological and pathophysiological factors in the intestine. The focus of OrBiTo is to characterize and predict the impact of both physical drug form (i) and formulation technology (ii) on bioavailability. These factors control drug release and dissolution in the GI tract. The composition, volumes of the GI fluids and hydrodynamic conditions generated by the GI motility which are controlled by endocrine and neural factors, also influence drug release and dissolution. However, the effect of dissolution on GI absorption is also modulated by a plethora of other factors involved in the drug absorption process (Fig 1). As an example, the overall impact of dissolution on GI drug absorption is strongly influenced by the effective intestinal permeability (Peff) (Bønløkke, 1999, 2001). In a similar fashion, capacity limited processes such as intestinal degradation and/or complexation, carrier-mediated transport and/or efflux processes through the intestinal wall,
294
H. Lennernäs et al. / European Journal of Pharmaceutical Sciences 57 (2014) 292–299
Stomach
Small Intestinal lumen Unreleased API Release solid released API
DP
Next compartments
Transit
Precipitation Dissolution Dissolved API Degradation
Absorption
Efflux Biliary excretion
API in enterocyte metabolism Metabolite
Portal vein
Liver
systemic circulation
metabolism Metabolite Fig. 1. Biopharmaceutical and physiological processes involved in GI drug absorption. Especially the dynamic changes along the GI tract are of major importance for the OrBiTo project to investigate with the aim to increase the mechanistic understanding.
metabolism in the intestinal mucosa, hepatic fist-pass metabolism, and lymphatic transport must all be considered to determine the impact of drug form and formulation on F. Moreover, many of these key processes are region specific and their impact will differ depending on the in vivo drug dissolution. Due to these regional differences, factors affecting GI transit of any pharmaceutical formulation are a key factors in the overall GI drug absorption. In a limited number of cases, pharmaceutical excipients have been shown to exert effects beyond dissolution/solubility including effects on intestinal Peff, metabolism and GI transit, as summarized for example by Lennernas and Abrahamsson (2005). Thus, in order to predict the influence of API’s physical form (i) and formulation technologies (ii) on GI drug absorption all of the factors described need to be taken into consideration. The OrBiTo project will take an integrated approach that fully considers the interplay among the above mentioned factors in order to improve the in vivo prediction of GI drug absorption. 3. ‘Biopharmaceutical aspects in oral pharmaceutical formulation development’ The importance of the API form and formulation on the clinical performance has been magnified by modern drug discovery approaches, which yield highly potent and selective API that exhibit challenging biopharmaceutical properties, e.g. low aqueous solubility, sometimes in combination with limited intestinal Peff (Lipinski, 2000). Such drugs often require complex formulation strategies to enable successful GI drug absorption and product development. These dosage forms are based on high energetic solid-state forms of the API, reduction of the API particle size (sometimes as far as the nano-scale), lipid formulations or soluble drug complexes (Williams, 2013). The biopharmaceutical behavior of such pharmaceutical products has to be carefully monitored throughout the drug development process. Accurate profiling of the biopharmaceutical characteristics of an API, such as permeability and solubility, has been established as key to candidate drug selection to ensure optimal developability properties. This collection of API properties also facilitates dose prediction to man, the selection of a product design providing optimal clinical properties, the maintenance of defined exposure-time profile in target patient group(s) after process optimization and manufacturing scale-up to commercial scale or after post-approval changes (Lennernas and Abrahamsson, 2005).
Another highly challenging area from a biopharmaceutical point of view is the increasing trend to develop modified release (MR) formulations to improve medical performance of the products. For MR formulations, drug release, dissolution and intestinal Peff require a larger part of the GI tract than immediate release (IR) dosage forms, which makes regional variation among absorption factors even more critical. Finally, the need to link formulation and manufacturing to clinical performance has received increased emphasis with the introduction of QbD, (Dickinson, 2008; ICH guideline, 2009). Today, biopharmaceutical investigations of API and formulation testing at different stages of drug discovery and development is still, to a very high degree, an empirical process rather than based on in depth mechanistic understanding. Typically traditional in vitro dissolution methods derived from quality control and in vivo testing in animals serve as the primary tools to guide development. At later stages, numerous human in vivo bioequivalence (BE) trials are performed to verify therapeutic equivalence based on systemic exposure-time profiles for different clinical trials and commercial formulation variants. Current manufacturing batch control tests generally serve their purpose well to assure sufficient quality for the patients. However, introducing more clinically relevant methods, especially in the context of QbD, could make manufacturing more cost-effective while maintaining or even improving quality for the patients. So there is a great need to develop an improved set of biopharmaceutics tools and to systematically validate existing approaches with respect to their performance in predicting the in vivo outcome. 4. Current status of predictive biopharmaceutics tools Most of the progress in understanding and predicting the GI absorption process during the last 15–20 years from an industrial perspective is represented by the introduction of in vitro permeability models (Artursson, 1990), biorelevant dissolution fluids (Dressman et al., 1998), the BCS (Amidon, 1995; Chen, 2011) and in silico PBPK models for integration of in vitro data and prediction of GI drug absorption (Agoram, 2001; Jamei, 2009; Dressman, 2011). However, these advances are not an end-point, but the first steps towards improved in vivo predictions (Larregieu and Benet, 2013). For example, in vitro permeability models are geared towards early screening decisions and qualitative investigations of carriermediated transporter processes. However, high quality in vivo
H. Lennernäs et al. / European Journal of Pharmaceutical Sciences 57 (2014) 292–299
predictions require quantitative estimates of human intestinal Peff from different regions (Lennernäs, 1998). The in vitro–in vivo correlation (IVIVC) between in vitro cell monolayer models, such as Caco-2, has over the years shown that drug transported by nutrient carriers such as amino acids, peptides and nucleoside are several fold higher in vivo in human jejunum than in vitro (Lennernas, 1996; Sun, 2002; Lennernäs, 1998; Larregieu and Benet, 2013). It is clear that the Caco-2 cell system is an example of an in vitro methodology that can only be directly correlated to human small intestinal permeability predictions when scaling factors are applied. Even if BCS class II drugs are better correlated regarding permeability some pose practical limitations for permeability determination due to very low solubility (Buckley, 2012). Improved approaches to obtain more accurate quantitative predictions of Peff require consideration of drug ionization changes along the GI tract, the correlation of in vitro and in vivo ‘‘unstirred water layer’’/mucus layer effects, a better understanding of how colloidal complexes of the drug (e.g. complexation to excipients, solubilization in micelles) or nanoparticulate forms influences the apparent permeability and consideration of regional differences in epithelial permeability. With respect to solubility and dissolution assessment, the use of biorelevant fluids, especially Fasted Simulated Small Intestinal Fluid (FaSSIF), has been well established within the pharmaceutical industry. However, this medium represents only the proximal jejunum, and hence cannot take into account the rapid and dynamic changes in the conditions along the intestine. Since the absorption of challenging compounds is typically not completed in the upper small intestine, the use of FASSIF alone may not be sufficient. It is also of interest to document the inter- and intra-individual variability in GI composition (Lindahl, 1997; Kalantzi, 2006) and in vitro dissolution in ex vivo GI fluids (Pedersen, 2000). Several encouraging reports have been published regarding the improved in vivo predictability provided by FaSSIF compared to traditional buffers (Dressman and Reppas, 2000). However, in general, all the approaches involving biorelevant media for simulation of the GI fluids lack systematic validation to elucidate limitations and to identify the need for additional improvement. A similar lack of systematic validation is limiting the use of both complex in vitro models (e.g. www.tno.nl, www.modelgut.com) and PBPK in silico models for simulation of GI drug absorption (e.g. www.simcyp.com, www.simulations-plus.com). Indeed, a recent study on PBPK modelling highlighted the strong need for better understanding of pharmaceutics/biopharmaceutics factors to improve predictions of GI drug absorption using these in silico tools (Poulin, 2011). The BCS represented a substantial shift in the drug development process by introducing the concept that in vitro methods can replace in vivo studies without prior establishment of an IVIVC in order to demonstrate BE. According to the revised EMA BE guideline from 2010, it is possible to grant biowaivers (i.e. demonstrating BE without in vivo tests) to BCS class I and III drugs (as very rapidly dissolving products). The possibility to extend BCS-based biowaivers to certain groups of class II drugs as well as to more slowly dissolving class I drugs (i.e.
Contents lists available at ScienceDirect
European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps
Review
Oral biopharmaceutics tools – Time for a new initiative – An introduction to the IMI project OrBiTo H. Lennernäs a, L. Aarons b, P. Augustijns c, S. Beato d, M. Bolger e, K. Box f, M. Brewster g, J. Butler h, J. Dressman i, R. Holm j, K. Julia Frank k, R. Kendall l, P. Langguth m, J. Sydor n, A. Lindahl o, M. McAllister p, U. Muenster q, A. Müllertz r, K. Ojala s, X. Pepin t, C. Reppas u, A. Rostami-Hodjegan v, M. Verwei w, W. Weitschies x, C. Wilson y, C. Karlsson z, B. Abrahamsson z,⇑ a
Uppsala University, Sweden University of Manchester, United Kingdom c Katholische University of Leuven, Belgium d Novartis, Switzerland e Simulations Plus, United States f Sirius Analytical, United Kingdom g Johnson & Johnson, Belgium h GSK, United Kingdom i Goethe University Frankfurt am Main, Germany j H. Lundbeck A/S, Denmark k Boehringer-Ingelheim, Germany l Merck, United Kingdom m Johannes Gutenberg University of Mainz, Germany n AbbVie, Germany o Medical Products Agency, Sweden p Pfizer, United Kingdom q Bayer Pharma AG, Germany r University of Copenhagen, Denmark s Orion Pharma, Finland t Sanofi-Aventis, France u National and Kapodistrian University of Athens, Greece v Simcyp Ltd/University of Manchester, United Kingdom w TNO, Netherlands x University of Greifswald, Germany y University of Strathclyde, United Kingdom z AstraZeneca R&D, Sweden b
a r t i c l e
i n f o
Article history: Received 19 June 2013 Received in revised form 22 October 2013 Accepted 24 October 2013 Available online 1 November 2013 Keywords: BCS PBPK IVIVC Dissolution Drug absorption Permeability
a b s t r a c t OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo
⇑ Corresponding author. Address: AstraZeneca R&D, S-43183 Mölndal, Sweden. E-mail address: [email protected] (B. Abrahamsson). 0928-0987/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejps.2013.10.012
293
H. Lennernäs et al. / European Journal of Pharmaceutical Sciences 57 (2014) 292–299
are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes. Ó 2013 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Intestinal absorption – definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ‘Biopharmaceutical aspects in oral pharmaceutical formulation development’ . Current status of predictive biopharmaceutics tools . . . . . . . . . . . . . . . . . . . . . . The novel IMI project: OrBiTo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction The Innovative Medicines Initiative (IMI) (http://www.imi.europa.eu/) is Europe’s largest public–private initiative in the life science sector between the European Union (EU) and the European pharmaceutical industry association (EFPIA). The aim is to speed up the development of better and safer medicines for patients and build networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. OrBiTo is a key initiative within IMI, designed to streamline and optimize the development of orally administered drug products with a strong focus to develop novel experimental and theoretical models to increase our knowledge of biopharmaceutical factors and their interplay with the dynamic gastrointestinal (GI) physiology (http://www.orbitoproject.eu, http://www.imi.europa.eu/content/ orbito). The project started October 1 2012 and will continue for five years and expected to start report novel findings during its second year. The OrBiTo project will address key gaps in our knowledge of GI drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through prospective studies to define new methodologies and to refine existing tools. Extensive validation of novel and existing tools will be performed using historical datasets from industry partners. A combination of high quality in vitro and in silico characterizations of active pharmaceutical ingredient (API) and formulations will be integrated into physiologically based in silico models capturing the full complexity of GI drug absorption. Thus, the OrBiTo project is expected to ‘‘change the game’’ in industrial product development from an essentially empirical approach (‘‘trial-and-error’’) to a more rational model-based approach. Scientific advances in the biopharmaceutical field will provide a step change in our ability to predict product in vivo performance in patients that will strongly impact the pharmaceutical development in a positive way. It may also provide the basis for revised regulatory guidelines in the context of Quality by Design (QbD) by providing reliable biopharmaceutics links between the API and its formulation on the one hand, and the patient and therapeutic goal on the other hand enabling more clinically relevant development targets and quality specifications. In order to achieve all of these goals, four separate work packages (WP1–4) have been created to develop suitable tools for characterizing the API, designing and characterizing the formulation, understanding the conditions in the GI tract better and optimizing the absorption aspects of physiologically based pharmacokinetic (PBPK) models. The objective of this overview is to describe the scope and objectives of the OrBiTo project. In the subsequent review articles
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293 293 294 294 295 298 298
in this special issue of European Journal of Pharmaceutical Sciences (EJPS), the status and gaps regarding in vivo predictive biopharmaceutics tools and the associated underlying science are addressed in more detail. 2. Intestinal absorption – definition Oral administration of pharmaceutical products is the preferred route for the majority of medical treatments. It is feasible and useful to evaluate the performance of orally administered drugs and dosage forms in the GI tract by analyzing the plasma drug exposure-time profile. The oral bioavailability (F) is one of the most useful pharmacokinetic (PK) parameters in this context and F is strongly related to the pharmacological effect and safety for systemically acting drug products. F is affected by a number of processes, discussed below. F is the result of three general processes: fraction dose absorbed across the apical cell membrane into the cellular space of the enterocyte, described as fa, intestinal first-pass metabolism (EG) and hepatic first-pass metabolism (EH) (Eq. (1)) (Rowland and Tozer, 1995).
F ¼ fa ð1 EG Þ ð1 EH Þ
ð1Þ
A schematic overview of most relevant processes involved is also provided in Fig. 1. The fraction of the dose absorbed (fa) is affected by various factors which influence drug release, dissolution, luminal degradation/complexation and intestinal wall permeability. In general, these factors can be grouped into three categories: (i) physico-chemical factors of the drug molecule itself, (ii) pharmaceutical factors such as design of formulations, including choice of excipients and the physical/solid state form of the drug in the final product, and (iii) physiological and pathophysiological factors in the intestine. The focus of OrBiTo is to characterize and predict the impact of both physical drug form (i) and formulation technology (ii) on bioavailability. These factors control drug release and dissolution in the GI tract. The composition, volumes of the GI fluids and hydrodynamic conditions generated by the GI motility which are controlled by endocrine and neural factors, also influence drug release and dissolution. However, the effect of dissolution on GI absorption is also modulated by a plethora of other factors involved in the drug absorption process (Fig 1). As an example, the overall impact of dissolution on GI drug absorption is strongly influenced by the effective intestinal permeability (Peff) (Bønløkke, 1999, 2001). In a similar fashion, capacity limited processes such as intestinal degradation and/or complexation, carrier-mediated transport and/or efflux processes through the intestinal wall,
294
H. Lennernäs et al. / European Journal of Pharmaceutical Sciences 57 (2014) 292–299
Stomach
Small Intestinal lumen Unreleased API Release solid released API
DP
Next compartments
Transit
Precipitation Dissolution Dissolved API Degradation
Absorption
Efflux Biliary excretion
API in enterocyte metabolism Metabolite
Portal vein
Liver
systemic circulation
metabolism Metabolite Fig. 1. Biopharmaceutical and physiological processes involved in GI drug absorption. Especially the dynamic changes along the GI tract are of major importance for the OrBiTo project to investigate with the aim to increase the mechanistic understanding.
metabolism in the intestinal mucosa, hepatic fist-pass metabolism, and lymphatic transport must all be considered to determine the impact of drug form and formulation on F. Moreover, many of these key processes are region specific and their impact will differ depending on the in vivo drug dissolution. Due to these regional differences, factors affecting GI transit of any pharmaceutical formulation are a key factors in the overall GI drug absorption. In a limited number of cases, pharmaceutical excipients have been shown to exert effects beyond dissolution/solubility including effects on intestinal Peff, metabolism and GI transit, as summarized for example by Lennernas and Abrahamsson (2005). Thus, in order to predict the influence of API’s physical form (i) and formulation technologies (ii) on GI drug absorption all of the factors described need to be taken into consideration. The OrBiTo project will take an integrated approach that fully considers the interplay among the above mentioned factors in order to improve the in vivo prediction of GI drug absorption. 3. ‘Biopharmaceutical aspects in oral pharmaceutical formulation development’ The importance of the API form and formulation on the clinical performance has been magnified by modern drug discovery approaches, which yield highly potent and selective API that exhibit challenging biopharmaceutical properties, e.g. low aqueous solubility, sometimes in combination with limited intestinal Peff (Lipinski, 2000). Such drugs often require complex formulation strategies to enable successful GI drug absorption and product development. These dosage forms are based on high energetic solid-state forms of the API, reduction of the API particle size (sometimes as far as the nano-scale), lipid formulations or soluble drug complexes (Williams, 2013). The biopharmaceutical behavior of such pharmaceutical products has to be carefully monitored throughout the drug development process. Accurate profiling of the biopharmaceutical characteristics of an API, such as permeability and solubility, has been established as key to candidate drug selection to ensure optimal developability properties. This collection of API properties also facilitates dose prediction to man, the selection of a product design providing optimal clinical properties, the maintenance of defined exposure-time profile in target patient group(s) after process optimization and manufacturing scale-up to commercial scale or after post-approval changes (Lennernas and Abrahamsson, 2005).
Another highly challenging area from a biopharmaceutical point of view is the increasing trend to develop modified release (MR) formulations to improve medical performance of the products. For MR formulations, drug release, dissolution and intestinal Peff require a larger part of the GI tract than immediate release (IR) dosage forms, which makes regional variation among absorption factors even more critical. Finally, the need to link formulation and manufacturing to clinical performance has received increased emphasis with the introduction of QbD, (Dickinson, 2008; ICH guideline, 2009). Today, biopharmaceutical investigations of API and formulation testing at different stages of drug discovery and development is still, to a very high degree, an empirical process rather than based on in depth mechanistic understanding. Typically traditional in vitro dissolution methods derived from quality control and in vivo testing in animals serve as the primary tools to guide development. At later stages, numerous human in vivo bioequivalence (BE) trials are performed to verify therapeutic equivalence based on systemic exposure-time profiles for different clinical trials and commercial formulation variants. Current manufacturing batch control tests generally serve their purpose well to assure sufficient quality for the patients. However, introducing more clinically relevant methods, especially in the context of QbD, could make manufacturing more cost-effective while maintaining or even improving quality for the patients. So there is a great need to develop an improved set of biopharmaceutics tools and to systematically validate existing approaches with respect to their performance in predicting the in vivo outcome. 4. Current status of predictive biopharmaceutics tools Most of the progress in understanding and predicting the GI absorption process during the last 15–20 years from an industrial perspective is represented by the introduction of in vitro permeability models (Artursson, 1990), biorelevant dissolution fluids (Dressman et al., 1998), the BCS (Amidon, 1995; Chen, 2011) and in silico PBPK models for integration of in vitro data and prediction of GI drug absorption (Agoram, 2001; Jamei, 2009; Dressman, 2011). However, these advances are not an end-point, but the first steps towards improved in vivo predictions (Larregieu and Benet, 2013). For example, in vitro permeability models are geared towards early screening decisions and qualitative investigations of carriermediated transporter processes. However, high quality in vivo
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predictions require quantitative estimates of human intestinal Peff from different regions (Lennernäs, 1998). The in vitro–in vivo correlation (IVIVC) between in vitro cell monolayer models, such as Caco-2, has over the years shown that drug transported by nutrient carriers such as amino acids, peptides and nucleoside are several fold higher in vivo in human jejunum than in vitro (Lennernas, 1996; Sun, 2002; Lennernäs, 1998; Larregieu and Benet, 2013). It is clear that the Caco-2 cell system is an example of an in vitro methodology that can only be directly correlated to human small intestinal permeability predictions when scaling factors are applied. Even if BCS class II drugs are better correlated regarding permeability some pose practical limitations for permeability determination due to very low solubility (Buckley, 2012). Improved approaches to obtain more accurate quantitative predictions of Peff require consideration of drug ionization changes along the GI tract, the correlation of in vitro and in vivo ‘‘unstirred water layer’’/mucus layer effects, a better understanding of how colloidal complexes of the drug (e.g. complexation to excipients, solubilization in micelles) or nanoparticulate forms influences the apparent permeability and consideration of regional differences in epithelial permeability. With respect to solubility and dissolution assessment, the use of biorelevant fluids, especially Fasted Simulated Small Intestinal Fluid (FaSSIF), has been well established within the pharmaceutical industry. However, this medium represents only the proximal jejunum, and hence cannot take into account the rapid and dynamic changes in the conditions along the intestine. Since the absorption of challenging compounds is typically not completed in the upper small intestine, the use of FASSIF alone may not be sufficient. It is also of interest to document the inter- and intra-individual variability in GI composition (Lindahl, 1997; Kalantzi, 2006) and in vitro dissolution in ex vivo GI fluids (Pedersen, 2000). Several encouraging reports have been published regarding the improved in vivo predictability provided by FaSSIF compared to traditional buffers (Dressman and Reppas, 2000). However, in general, all the approaches involving biorelevant media for simulation of the GI fluids lack systematic validation to elucidate limitations and to identify the need for additional improvement. A similar lack of systematic validation is limiting the use of both complex in vitro models (e.g. www.tno.nl, www.modelgut.com) and PBPK in silico models for simulation of GI drug absorption (e.g. www.simcyp.com, www.simulations-plus.com). Indeed, a recent study on PBPK modelling highlighted the strong need for better understanding of pharmaceutics/biopharmaceutics factors to improve predictions of GI drug absorption using these in silico tools (Poulin, 2011). The BCS represented a substantial shift in the drug development process by introducing the concept that in vitro methods can replace in vivo studies without prior establishment of an IVIVC in order to demonstrate BE. According to the revised EMA BE guideline from 2010, it is possible to grant biowaivers (i.e. demonstrating BE without in vivo tests) to BCS class I and III drugs (as very rapidly dissolving products). The possibility to extend BCS-based biowaivers to certain groups of class II drugs as well as to more slowly dissolving class I drugs (i.e.
