Christos Reppas

Harokopion University of Athens, Athínai, Attica, Greece

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Publications (102)339.59 Total impact

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    ABSTRACT: Purpose: Design an in vitro methodology for studying gastrointestinal transfer in the fasted state and implement the methodology in vitro by using a biorelevant gastrointestinal transfer system (BioGIT); evaluate the usefulness of BioGIT in predicting luminal concentrations of lipophilic weak bases in the fasted upper small intestine. Methods: The methodology was designed after modeling existing luminal data. Its implementation in vitro was based on a three compartment setup. Reproducibility of the transfer process was evaluated under conditions where solutions and/or suspensions were present in gastric and/or duodenal compartment and by using ranitidine, dipyridamole, ketoconazole, and posaconazole as model drugs. The transfer process as well as concentrations of dipyridamole, ketoconazole and posaconazole measured in the duodenal compartment were compared with data previously collected in the upper small intestine, after administration of identical preparations/dosage forms to fasted adults. Results: Using BioGIT, the transfer process was performed reproducibly in all cases (RSD < 12.9%); data with dipyridamole and ketoconazole were in line with luminal data in humans. Dipyridamole, ketoconazole and posaconazole concentrations in duodenal compartment were also in line with previously measured concentrations in the fasted upper small intestine of healthy adults. Conclusions: BioGIT system could be useful for the evaluation of the impact of gastrointestinal transfer on concentrations in the upper intestinal lumen during the first hour, after oral administration of dispersing/solution dosage forms of lipophilic weak bases.
    No preview · Article · Nov 2015 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
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    ABSTRACT: Aims Postprandial administration of solid oral dosage forms greatly changes the dissolution environment compared to fasted state administration. The aims of this study were to investigate and forecast the effect of co-administration of a meal on drug release for delayed and/or extended release mesalamine formulations as well as design of in vitro tests to distinguish among formulations in a biorelevant way. Methods Five different mesalamine formulations (Asacol® 400 mg, Mezavant® 1200 mg, Pentasa® 500 mg and Salofalk® in the 250 mg and 500 mg strengths) were investigated with biorelevant dissolution methods using the USP apparatus III and USP apparatus IV (open loop mode) under both fasted and fed state conditions, as well as with the dissolution methods described in pharmacopeia for delayed and extended release mesalamine products. Results Using the biorelevant experimental conditions proposed in this study, changes in release in the proximal gut due to meal intake are forecast to be minimal for Asacol®, Mezavant®, Pentasa® and Salofalk® 500 mg, while for Salofalk® 250 mg release was predicted to occur much earlier under fed state conditions. The USP apparatus III generally tended to result in faster dissolution rates and forecast more pronounced food effects for Salofalk® 250 mg than the USP apparatus IV. The biorelevant dissolution gradients were also able to reflect the in vivo behavior of the formulations. Conclusions In vitro biorelevant models can be useful in the comparison of the release behavior from different delayed and extended release mesalamine formulations as well as forecasting effects of concomitant meal intake on drug release.
    No preview · Article · Nov 2015 · European Journal of Pharmaceutics and Biopharmaceutics
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    ABSTRACT: The objective of this study was to develop an in vitro dissolution test method with discrimination ability for an extended-release solid dispersion matrix of a lipophilic drug with the United States Pharmacopeia (USP) Apparatus 4, flow-through cell apparatus. In the open-loop configuration, the sink condition was maintained by manipulation of the flow rate of dissolution medium. To evaluate the testing conditions, the drug release mechanism from an extended-release solid dispersion matrix containing hydrophobic and hydrophilic polymers was investigated. As the hydrophilic hydroxypropyl methylcellulose (HPMC) maintained concentrations higher than the solubility of indomethacin in a dissolution medium, the release of HPMC into the dissolution medium was also quantified using size-exclusion chromatography. We therefore concluded that the USP Apparatus 4 was suitable for application to an in vitro dissolution method for an orally administered extended-release solid dispersion matrix formulation containing poorly water-soluble drugs. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · May 2015 · International Journal of Pharmaceutics
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    ABSTRACT: Characterize the contents of distal ileum and cecum in healthy adults under conditions simulating the bioavailability/bioequivelance studies of drug products in fasted and fed state. Twelve males participated in a two-phase crossover study. Phase I: subjects remained fasted overnight plus 4.5 h in the morning prior to colonoscopy. Phase II: subjects remained fasted overnight, consumed breakfast in the morning, and abstain from food until colonoscopy, 4.5 h after breakfast. Upon sampling, volume, pH and buffer capacity were measured; after ultracentrifugation, supernatant was physicochemically characterized and non-liquid particles diameter was measured. In distal ileum, pH is ~8.1 and size of non-liquid particles is ~200 μm, regardless of dosing conditions; in fed state, liquid fraction was lower whereas osmolality and carbohydrate content were higher. In cecum, the environment was similar with previously characterized environment in the ascending colon; in fasted state, size of non-liquid particles is smaller than in distal ileum (~70 μm). Fluid composition in distal ileum is different from cecum, especially in fasted state. Differences in luminal environment between distal ileum and cecum may impact the performance of orally administered products which deliver drug during residence in lower intestine. Dosing conditions affect cecal environment more than in distal ileum.
    No preview · Article · May 2015 · Pharmaceutical Research
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    ABSTRACT: The purpose was to propose two-stage single-compartment models for evaluating dissolution characteristics in distal ileum and ascending colon, under conditions simulating the bioavailability and bioequivalence studies in fasted and fed state by using the mini-paddle and the compendial flow-through apparatus (closed-loop mode). Immediate release products of two highly dosed active pharmaceutical ingredients (APIs), sulfasalazine and L-870,810, and one mesalamine colon targeting product were used for evaluating their usefulness. Change of medium composition simulating the conditions in distal ileum (SIFileum ) to a medium simulating the conditions in ascending colon in fasted state and in fed state was achieved by adding an appropriate solution in SIFileum . Data with immediate release products suggest that dissolution in lower intestine is substantially different than in upper intestine and is affected by regional pH differences > type/intensity of fluid convection > differences in concentration of other luminal components. Asacol® (400 mg/tab) was more sensitive to type/intensity of fluid convection. In all the cases, data were in line with available human data. Two-stage single-compartment models may be useful for the evaluation of dissolution in lower intestine. The impact of type/intensity of fluid convection and viscosity of media on luminal performance of other APIs and drug products requires further exploration. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
    No preview · Article · May 2015 · Journal of Pharmaceutical Sciences
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    ABSTRACT: Evaluate the impact of salt and counterion identity on performance of solid immediate release dosage forms of miconazole and clopidogrel, respectively, in fasted upper gastrointestinal lumen using in-vitro methodologies. Two miconazole chemical forms (free base and nitrate salt) and three clopidogrel chemical forms (bisulfate, besylate and hydrochloride salts) were studied. Solubilities of miconazole forms were measured in simulated gastric fluids. Gastrointestinal transfer of the five chemical forms was evaluated by using a flow-through, three-compartmental set-up. Precipitation in duodenal compartment was evaluated by using solutions in gastric compartment. Solubilities in simulated gastric fluids, concentrations in duodenal compartment and solubilities in duodenal compartment indicated poorer performance of miconazole nitrate vs. miconazole free base in upper gastrointestinal lumen. In line with the low crystallization tendency of free base, duodenal precipitation of miconazole from a free base solution was limited. Concentrations in duodenal compartment indicated that counterion identity does not affect the performance of clopidogrel; precipitation in duodenal compartment was extensive in all cases. Miconazole data indicate that salts may adversely affect performance of immediate release dosage forms of weak bases. In line with existing in-vivo data, clopidogrel data indicate that counterion identity is unimportant for the performance of clopidogrel salts in upper intestinal lumen. © 2015 Royal Pharmaceutical Society.
    No preview · Article · Apr 2015
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    ABSTRACT: Biorelevant media for evaluation of dosage form performance in the gastrointestinal lumen were first introduced in the late 1990s. Since then, a variety of additional media have been proposed, making it now possible to simulate most regions in the gastrointestinal tract in both prandial states. However, recent work suggests that the complexity and degree of biorelevance required to predict in-vivo release varies with the drug, dosage form and dosing conditions. The aim of this commentary is to establish which levels of biorelevant media are appropriate to various combinations of active pharmaceutical ingredient(s), dosage form and dosing conditions. With regard to their application, a decision tree for the selection of the appropriate biorelevant medium/media is proposed and illustrative case scenarios are provided. Additionally, media to represent the distal small intestine in both prandial states are presented. The newly proposed levels of biorelevance and accompanying decision tree may serve as a useful tool during formulation development in order to ensure high quality, predictive performance results without unnecessary complexity of media. In future work, further specific case examples will be evolved, which will additionally address the need to take the hydrodynamics and passage times into consideration. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Mar 2015 · European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
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    ABSTRACT: Objectives This paper aims to study the features of colloidal species in the lumen of the upper small intestine of two healthy adults at fasted state by means of electron microscopy.Methods Samples were aspirated from a location near the ligament of Treitz 30 min (volunteer no. 1, Aspirate30min sample) and 60 min (volunteer no. 2, Aspirate60min sample), after administration of 240 ml of an aqueous solution in the fasted state.Key findingsIn the Aspirate30min sample micelles coexist with multi-, oligo- and unilamellar vesicles. Tubular structures and long structures were frequently visualised. In the Aspirate60min sample micelles, few unilamellar vesicles, long structures and tubular structures were the dominating structural features. In both samples, multivesicular structures and faceted vesicles (previously visualised at fed state) were absent. Structural features of both samples bear similarities with previously studied samples from the lower intestine in the fasted state. Micelles and unilamellar vesicles observed in both samples closely resemble morphological characteristics of those found in fluids simulating the colloidal species in fasted upper intestinal environment.Conclusions Features of colloidal species in contents of fasted small intestine have similarities with fluids simulating the contents in fasted upper small intestine and with contents of lower intestine in the fasted state.
    No preview · Article · Feb 2015
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    ABSTRACT: Objectives Evaluate the ability of biorelevant media to adequately predict solubility in human gastrointestinal aspirates collected in the fasted state for the sodium salt of a highly dosed, Biopharmaceutics Classification System II (BCS II) compound with weakly acidic properties (L-870,810, pKa 7.3, HA (5-(1,1-dioxothiazinan-2-yl)-N-((4-fluorophenyl)methyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide)). Identify key luminal processes that dictate the behaviour of sodium salt of HA (NaA), after single-dose administrations of high (relatively to solubility limit) doses corresponding to 400 and 800 mg of HA in the fasted state.Methods Aspirates from stomach and upper small intestine were collected from eight healthy fasted adults, after administration of 240 ml of water. Solubilities of NaA and HA were measured in aspirated samples and biorelevant media. Dissolution experiments of NaA granules were performed in biorelevant media. Prediction of oral pharmacokinetics was evaluated in silico using Stella software.Key findingsEquilibrium solubility of NaA in fluids aspirated from the upper gastrointestinal tract is more transient than of HA. Solubility in upper gastrointestinal lumen was adequately estimated by data in biorelevant media. Supersaturation, followed by precipitation, which did not fully revert to the equilibrium solubility of HA, was observed during the dissolution of NaA granules in biorelevant media. Physiologically based pharmacokinetic modelling indicated that while intragastric processes had no significant impact on absorption kinetics, dissolution kinetics, kinetic solubility, radial transport rates and, for the 800-mg dose, precipitation kinetics in the small intestine had the greatest impact on absorption profiles.Conclusions Adequate prediction of the average plasma profile, after administration of NaA, required consideration of region-dependent dissolution rates and/or solubilisation.
    Preview · Article · Oct 2014
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    ABSTRACT: Introduction: The purpose of this study was to explore the transfer of drug solutions from stomach to small intestine and its impact on intraluminal drug concentrations in humans. The collected intraluminal data were used as reference to evaluate simulations of gastrointestinal transfer currently implemented in different in vitro and in silico absorption models. Methods: Gastric and duodenal concentrations of the highly soluble and non-absorbable compound paromomycin were determined following oral administration to 5 healthy volunteers under the following conditions: fasted state, fed state and fed state in the presence of a transit-stimulating (domperidone) or transit-inhibiting (loperamide) agent. Based on the obtained intraluminal concentration-time profiles, gastrointestinal transfer (expressed as the half-life of gastric emptying) was analyzed using physiologically-based parameter estimation in Simcyp®. Subsequently, the observed transfer profiles were used to judge the implementation of gastrointestinal transfer in 2 in vitro simulation tools (the TNO Intestinal Model TIM-1 and a three-compartmental in vitro model) and the Simcyp® population-based PBPK modeling platform. Results: The observed duodenal concentration-time profile of paromomycin under fasting conditions, with a high average Cmax obtained after 15 min, clearly indicated a fast transfer of drug solutions from stomach to duodenum (estimated gastric half-life between 4 and 13 min). The three-compartmental in vitro model adequately reflected the in vivo fasted state gastrointestinal transfer of paromomycin. For both TIM-1 and Simcyp®, modifications in gastric emptying and dilutions were required to improve the simulation of the transfer of drug solutions. As expected, transfer from stomach to duodenum was delayed in the fed state, resulting in lower duodenal paromomycin concentrations and an estimated gastric half-life between 21 and 40 min. Administration of domperidone or loperamide as transit-stimulating and transit-inhibiting agent, respectively, did not affect the fed state gastric half-life of emptying. Conclusion: For the first time, the impact of gastrointestinal transfer of solutions on intraluminal drug concentrations was directly assessed in humans. In vitro and in silico simulation tools have been validated and optimized using the in vivo data as reference.
    Full-text · Article · Jul 2014 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
  • Nikolaos Koumandrakis · Maria Vertzoni · Christos Reppas

    No preview · Article · Jul 2014
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    ABSTRACT: Biorelevant in vitro performance testing of orally administered dosage forms has become an important tool for the assessment of drug product in vivo behavior. An in vitro performance test which mimics the intraluminal performance of an oral dosage form is termed biorelevant. Biorelevant tests have been utilized to decrease the number of in vivo studies required during the drug development process and to mitigate the risk related to in vivo bioequivalence studies. This report reviews the ability of current in vitro performance tests to predict in vivo performance and generate successful in vitro and in vivo correlations for oral dosage forms. It also summarizes efforts to improve the predictability of biorelevant tests. The report is based on the presentations at the 2013 workshop, Biorelevant In Vitro Performance Testing of Orally Administered Dosage Forms, in Washington, DC, sponsored by the FIP Dissolution/Drug Release Focus Group in partnership with the American Association of Pharmaceutical Scientists (AAPS) and a symposium at the AAPS 2012 Annual meeting on the same topic.
    No preview · Article · Mar 2014 · Pharmaceutical Research
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    ABSTRACT: 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 todays 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.
    No preview · Article · Mar 2014 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
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    ABSTRACT: 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 organisation, 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 and. 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 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) and modified-release formulations, as well as allowing optimisation of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo is 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.
    No preview · Article · Nov 2013 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
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    ABSTRACT: In this work we developed and characterized transport media that simulate the composition of micellar phase of intestinal fluids in the fasted and, especially, in the fed state and are appropriate for evaluating intestinal drug permeability characteristics using the Caco-2 model (FaSSIF-TMCaco and FeSSIF-TMCaco, respectively). Media composition was based on FaSSIF-V2 and FeSSIF-V2 and recently reported data on total lipid concentrations in the micellar phase of contents of the upper small intestine in the fasted and the fed state and was adapted for cell culture compatibility. Permeation data were evaluated by compartmental kinetic modeling. Permeability coefficients, P, of hydrophilic drugs were not affected by media composition. In contrast, P values of a series of lipophilic compounds measured with FaSSIF-TMCaco and FeSSIF-TMCaco, and reflecting transport by diffusion were smaller than those obtained with a purely aqueous reference transport medium, aq-TMCaco, following the rank order aq-TMCaco > FaSSIF-TMCaco > FeSSIF-TMCaco. The decline of permeability values was stronger as lipophilicity of the compounds increased. Compared with values estimated using aq-TMCaco, permeability was reduced, depending on the compound, by more than 20- to 100-fold when measured with FeSSIF-TMCaco whereas compound ranking in regard to the permeability characteristics was also affected. The impact of reduced P value on flux through the mucosa, hence on drug absorption, in combination with the drug amount loaded on colloidal particles needs to be taken into consideration in PBPK modeling especially when the food effect is evaluated.
    Full-text · Article · Oct 2013 · European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
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    ABSTRACT: The objectives of this study were to characterise three prototype fenofibrate lipid-based formulations using a range of in vitro tests with differing levels of complexity and to assess the extent to which these methods provide additional insight into in vivo findings. Three self-emulsifying drug delivery systems (SEDDS) were prepared: a long chain (LC) Type IIIA SEDDS, a medium chain (MC) Type IIIA SEDDS, and a Type IIIB/IV SEDDS containing surfactants only (SO). Dilution, dispersion and digestion tests were performed to assess solubilisation and precipitation behaviour in vitro. Focussed beam reflectance measurements and solid state characterisation of the precipitate was conducted. Oral bioavailability was evaluated in landrace pigs. Dilution and dispersion testing revealed that all three formulations were similar in terms of maintaining fenofibrate in a solubilised state on dispersion in biorelevant media. During in vitro digestion, the Type IIIA formulations displayed limited drug precipitation (<5%), whereas the Type IIIB/IV formulation displayed extensive drug precipitation (∼70% dose). Solid state analysis confirmed that precipitated fenofibrate was crystalline. The oral bioavailability was similar for the three lipid formulations (65-72%). In summary, the use of LC versus MC triglycerides in Type IIIA SEDDS had no impact on the bioavailability of fenofibrate. The extensive precipitation observed with the Type IIIB/IV formulation during in-vitro digestion did not adversely impact fenofibrate bioavailability in-vivo, relative to the Type IIIA formulations. These results were predicted suitably using in vitro dilution and dispersion testing, whereas the in vitro digestion method failed to predict the outcome of the in vivo study.
    Full-text · Article · Oct 2013 · European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
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    ABSTRACT: Studies on the characterization of ascending colonic fluids are scarce, limited to physicochemical characterization of their composition, and little is known for the morphology of the produced colloidal phases. In an attempt to gain insights for their structure at the ultrastructural level, samples from the lumen of ascending colon were collected from patients with ulcerative colitis in remission. After ultracentrifugation, the supernatants of two samples (one with high and one with low cholesterol level) were visualized by means of cryogenic transmission electron microscopy. In the supernatants with high cholesterol content, micellar-like structures, bilayer fragments, open vesicles, and uni-, bi- and trilamellar vesicles were abundant. In addition, crystals of cholesterol were frequently observed. In contrast, in the sample with low cholesterol content, oily solids, plates of cholesterol monohydrate and elongated structures were present. Few unilamellar vesicles were occasionally visualized. The current study gives direct evidence, for the first time, of the existence of 'remnants' of lipolytic products in the fasted ascending colon. The impact of these structures to colonic absorption of drugs is an open question.
    No preview · Article · Oct 2013
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    ABSTRACT: Evaluate the impact of luminal micellar phase on passive permeability of five lipophilic (1.9 ≤ clogP ≤ 9.0) small molecules using biorelevant media and evaluate the impact of luminal coarse lipid particles on danazol permeability after oral administration of a triglyceride solution to fed adults using PAMPA. Permeability of carbamazepine, furosemide, danazol, and Compound A was evaluated using Prisma™ HT, FaSSIF-V2, and FeSSIF-V2 in the donor compartment. Compound B could not be tested using Prisma™ HT, due to negligible solubility. Individual intestinal aspirates collected after administration of danazol solution in the olive oil portion of a meal and corresponding micellar phases were subjected to PAMPA. Commercially available Acceptor Sink Buffer was used in all cases. Unlike with furosemide (under constant pH) and Compound B, permeability of carbamazepine, danazol, and Compound A steadily decreased in the presence of increasing micelle concentration of media. Danazol permeability from aspirates was reduced compared to that from micellar phases; fluxes were similar. Using PAMPA, the impact of luminal micellar phase on passive permeability of lipophilic molecules varies with the molecule. After administration of a triglyceride solution of danazol, high danazol concentrations in coarse lipid particles balance in terms of drug flux the reduced permeability.
    Full-text · Article · Jul 2013 · Pharmaceutical Research
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    ABSTRACT: Human biorelevant media have been shown to be a useful tool in pharmaceutical development and to provide input for in silico prediction of pharmacokinetic profiles after oral dosing. Dogs, in particular Beagles, are often used as animal models for preclinical studies. Key differences in the composition of human and canine gastric and intestinal fluids are described in literature and underscore the need to develop a discrete set of biorelevant media, adapted to the conditions of the proximal canine gastrointestinal (GI) tract, to improve forecast and interpretation of preclinical results using in vitro dissolution studies. Canine biorelevant media can also be used in the development of oral dosage forms for companion animals, which is a rapidly growing market. The compositions of Fasted State Simulated Gastric Fluid canine (FaSSGFc) and Fasted State Simulated Intestinal Fluid canine (FaSSIFc) are adapted to the physiological composition of the corresponding gastrointestinal fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid, and free fatty acid content (in terms of concentration and reported subtypes). It was demonstrated that canine Fasted State Simulated Intestinal Fluid (FaSSIFc) is superior in predicting the solubility of model compounds in Canine Intestinal Fluid (CIF) compared to the human biorelevant media (FaSSIF and FaSSIF-V2). Two different versions of FaSSGFc, composed at pH 1.5 and pH 6.5, offer the possibility to design in vitro studies which correspond to the in vivo study design, depending on whether pentagastrin is used to decrease the gastric pH in the dogs or not. Canine biorelevant media can therefore be recommended to achieve more accurate forecasting and interpretation of pharmacokinetic studies of oral drug products in dogs.
    No preview · Article · Feb 2013 · European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V
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    ABSTRACT: Purpose: To develop an in vitro methodology for prediction of concentrations and potential precipitation of highly permeable, lipophilic weak bases in fasted upper small intestine based on ketoconazole and dipyridamole luminal data. Evaluate usefulness of methodology in predicting luminal precipitation of AZD0865 and SB705498 based on plasma data. Methods: A three-compartment in vitro setup was used. Depending on the dosage form administered in in vivo studies, a solution or a suspension was placed in the gastric compartment. A medium simulating the luminal environment (FaSSIF-V2plus) was initially placed in the duodenal compartment. Concentrated FaSSIF-V2plus was placed in the reservoir compartment. Results: In vitro ketoconazole and dipyridamole concentrations and precipitated fractions adequately reflected luminal data. Unlike luminal precipitates, in vitro ketoconazole precipitates were crystalline. In vitro AZD0865 data confirmed previously published human pharmacokinetic data suggesting that absorption rates are not affected by luminal precipitation. In vitro SB705498 data predicted that significant luminal precipitation occurs after a 100 mg or 400 mg but not after a 10 mg dose, consistent with human pharmacokinetic data. Conclusions: An in vitro methodology for predicting concentrations and potential precipitation in fasted upper small intestine, after administration of highly permeable, lipophilic weak bases in fasted upper small intestine was developed and evaluated for its predictability in regard to luminal precipitation.
    No preview · Article · Aug 2012 · Pharmaceutical Research

Publication Stats

4k Citations
339.59 Total Impact Points

Institutions

  • 2009-2015
    • Harokopion University of Athens
      Athínai, Attica, Greece
  • 2000-2015
    • National and Kapodistrian University of Athens
      • • Department of Pharmaceutical Technology
      • • Faculty of Pharmacy
      • • Division of Pharmacology
      Athínai, Attica, Greece
  • 1990-2007
    • University of Michigan
      • College of Pharmacy
      Ann Arbor, Michigan, United States
  • 1994
    • Goethe-Universität Frankfurt am Main
      • Institut für Pharmazeutische Technologie
      Frankfurt am Main, Hesse, Germany