Publications by authors named "Joachim Brouwers"

86 Publications

Investigating the Mechanisms behind the Positive Food Effect of Abiraterone Acetate: In Vitro and Rat In Situ Studies.

Pharmaceutics 2022 Apr 28;14(5). Epub 2022 Apr 28.

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Gasthuisberg O&N II, Herestraat 49, P.O. Box 921, 3000 Leuven, Belgium.

The anticancer agent abiraterone suffers from an extensive positive food effect after oral intake of the prodrug abiraterone acetate (Zytiga). The underlying processes determining postprandial abiraterone absorption were investigated in this study. The impact of lipids and lipid digestion products on (i) the solubility of abiraterone acetate and abiraterone, (ii) the conversion of abiraterone acetate to abiraterone, and (iii) the passive permeation of abiraterone was determined in vitro. The interaction of abiraterone acetate and abiraterone with vesicles and colloidal structures in the simulated fed state media containing undigested lipids and lipid digestion products enhanced the solubility of both compounds but limited the esterase-mediated hydrolysis of abiraterone acetate and the potential of abiraterone to permeate. Rat in situ intestinal perfusion experiments with a suspension of abiraterone acetate in static fed state simulated media identified abiraterone concentrations in the perfusate as the main driving force for absorption. However, experiments with ongoing lipolysis in the perfusate highlighted the importance of including lipid digestion as a dynamic process when studying postprandial abiraterone absorption. Future research may employ the in situ perfusion model to study postprandial drug absorption from a dynamic lipolysis-mediated intestinal environment to provide reference data for the optimisation of relevant in vitro models to evaluate food effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics14050952DOI Listing
April 2022

Structured solubility behaviour in bioequivalent fasted simulated intestinal fluids.

Eur J Pharm Biopharm 2022 Jul 20;176:108-121. Epub 2022 May 20.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom. Electronic address:

Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2022.05.010DOI Listing
July 2022

Orlistat disposition in the human jejunum and the effect of lipolysis inhibition on bile salt concentrations and composition.

Int J Pharm 2022 Jun 6;621:121807. Epub 2022 May 6.

Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium. Electronic address:

The lipolysis-mediated postprandial small intestinal environment is known to influence the solubilisation and subsequent absorption of lipophilic drugs. In a previously performed small-scale clinical study in healthy volunteers, co-administration of the lipase inhibitor orlistat increased jejunal solubilisation and systemic absorption of fenofibrate after intake of the lipid-based formulation Fenogal. In the present study, the jejunal disposition of the locally acting orlistat was assessed and linked to fenofibrate solubilisation. In addition, the effect of orlistat-induced lipolysis inhibition on bile salt concentrations and composition was evaluated. Orlistat was distributed predominantly in the lipid layer, as indicated by a 5- to 14-fold higher AUC in the total jejunal samples as compared to the micellar layers. No effect of orally administered orlistat on bile salt composition or total concentrations (ranging from 1.5 to 24.8 mM and 1.8 to 33.2 mM with and without orlistat co-administration, respectively) could be observed. The intraluminal presence of orlistat in the total jejunal samples correlated with the increased fenofibrate solubilisation in the jejunum (r = 0.9344) and enhanced absorption (r = 0.8184), highlighting the importance of the intraluminal lipid phase in lipophilic drug absorption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2022.121807DOI Listing
June 2022

The effect of esomeprazole on the upper GI tract release and systemic absorption of mesalazine from colon targeted formulations.

Int J Pharm 2022 May 23;619:121701. Epub 2022 Mar 23.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - box 921, 3000 Leuven, Belgium. Electronic address:

The aim of the present study was to investigate the effect of coadministration of the proton pump inhibitor (PPI) esomeprazole on the upper GI tract behavior and systemic exposure of mesalazine from two mechanistically different colon targeted delivery systems: Claversal (pH-dependent release) and Pentasa (prolonged release). To this end, gastric, jejunal and systemic concentrations of mesalazine and its metabolite N-acetyl mesalazine were monitored in 5 healthy volunteers following oral intake of Pentasa or Claversal with or without PPI pre-treatment (cross-over study). Our exploratory study demonstrated that pre-treatment with a PPI may affect the release and absorption of mesalazine from formulations with different modified release mechanisms. Upon intake of Claversal, the onset of mesalazine absorption was accelerated substantially by PPI pre-treatment. While the PPI-induced increase in pH initiated the disintegration process already in the upper GI tract, the release of mesalazine started beyond the proximal jejunum. Upon intake of Pentasa, PPI pre-treatment seemed to increase the systemic exposure, even though the underlying mechanism could not be revealed yet. The faster release of mesalazine in the GI tract and/or the increased systemic absorption following PPI pre-treatment may reduce the ability of mesalazine to reach the colon. Future research assessing mesalazine disposition in the lower GI tract is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2022.121701DOI Listing
May 2022

Practical and operational considerations related to paediatric oral drug formulation: An industry survey.

Int J Pharm 2022 Apr 16;618:121670. Epub 2022 Mar 16.

Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium. Electronic address:

For over 15 years, US and EU regulations ensure that medicines developed for children are explicitly authorised for such use with age-appropriate forms and formulations, implying dedicated research. To shed light on how these regulations have been adopted by pharmaceutical companies and how various aspects of paediatric oral drug formulation development are currently handled, an exploratory survey was conducted. Topics included: general company policy, regulatory aspects, dosage form selection, in-vitro, in-silico and (non-)clinical in-vivo methods, and food effects assessment. The survey results clearly underline the positive impact of the paediatric regulations and their overall uptake across the pharmaceutical industry. Even though significant improvements have been made in paediatric product development, major challenges remain. In this respect, dosage form selection faces a discrepancy between the youngest age groups (liquid products preference) and older subpopulations (adult formulation preference). Additionally, concerted research is needed in the development and validation of in-vitro tools and physiology based pharmacokinetic models tailored to the paediatric population, and in estimating the effect of non-standard and paediatric relevant foods. The current momentum in paediatric drug development and research should allow for an evolution in standardised methodology and guidance to develop paediatric formulations, which would benefit pharmaceutical industry and regulators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2022.121670DOI Listing
April 2022

The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation.

Pharmaceutics 2022 Jan 4;14(1). Epub 2022 Jan 4.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49-Box 921, 3000 Leuven, Belgium.

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic T between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics14010119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8781256PMC
January 2022

Best practices in current models mimicking drug permeability in the gastrointestinal tract - An UNGAP review.

Eur J Pharm Sci 2022 Mar 22;170:106098. Epub 2021 Dec 22.

School of Pharmacy, University College Cork, Cork, Ireland.

The absorption of orally administered drug products is a complex, dynamic process, dependant on a range of biopharmaceutical properties; notably the aqueous solubility of a molecule, stability within the gastrointestinal tract (GIT) and permeability. From a regulatory perspective, the concept of high intestinal permeability is intrinsically linked to the fraction of the oral dose absorbed. The relationship between permeability and the extent of absorption means that experimental models of permeability have regularly been used as a surrogate measure to estimate the fraction absorbed. Accurate assessment of a molecule's intestinal permeability is of critical importance during the pharmaceutical development process of oral drug products, and the current review provides a critique of in vivo, in vitro and ex vivo approaches. The usefulness of in silico models to predict drug permeability is also discussed and an overview of solvent systems used in permeability assessments is provided. Studies of drug absorption in humans are an indirect indicator of intestinal permeability, but both in vitro and ex vivo tools provide initial screening approaches and are important tools for assessment of permeability in drug development. Continued refinement of the accuracy of in silico approaches and their validation with human in vivo data will facilitate more efficient characterisation of permeability earlier in the drug development process and will provide useful inputs for integrated, end-to-end absorption modelling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2021.106098DOI Listing
March 2022

Integration of advanced methods and models to study drug absorption and related processes: An UNGAP perspective.

Eur J Pharm Sci 2022 May 20;172:106100. Epub 2021 Dec 20.

Division of Pharmacology and Pharmacotherapy, University of Helsinki, Finland. Electronic address:

This collection of contributions from the European Network on Understanding Gastrointestinal Absorption-related Processes (UNGAP) community assembly aims to provide information on some of the current and newer methods employed to study the behaviour of medicines. It is the product of interactions in the immediate pre-Covid period when UNGAP members were able to meet and set up workshops and to discuss progress across the disciplines. UNGAP activities are divided into work packages that cover special treatment populations, absorption processes in different regions of the gut, the development of advanced formulations and the integration of food and pharmaceutical scientists in the food-drug interface. This involves both new and established technical approaches in which we have attempted to define best practice and highlight areas where further research is needed. Over the last months we have been able to reflect on some of the key innovative approaches which we were tasked with mapping, including theoretical, in silico, in vitro, in vivo and ex vivo, preclinical and clinical approaches. This is the product of some of us in a snapshot of where UNGAP has travelled and what aspects of innovative technologies are important. It is not a comprehensive review of all methods used in research to study drug dissolution and absorption, but provides an ample panorama of current and advanced methods generally and potentially useful in this area. This collection starts from a consideration of advances in a priori approaches: an understanding of the molecular properties of the compound to predict biological characteristics relevant to absorption. The next four sections discuss a major activity in the UNGAP initiative, the pursuit of more representative conditions to study lumenal dissolution of drug formulations developed independently by academic teams. They are important because they illustrate examples of in vitro simulation systems that have begun to provide a useful understanding of formulation behaviour in the upper GI tract for industry. The Leuven team highlights the importance of the physiology of the digestive tract, as they describe the relevance of gastric and intestinal fluids on the behaviour of drugs along the tract. This provides the introduction to microdosing as an early tool to study drug disposition. Microdosing in oncology is starting to use gamma-emitting tracers, which provides a link through SPECT to the next section on nuclear medicine. The last two papers link the modelling approaches used by the pharmaceutical industry, in silico to Pop-PK linking to Darwich and Aarons, who provide discussion on pharmacometric modelling, completing the loop of molecule to man.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2021.106100DOI Listing
May 2022

Fasted intestinal solubility limits and distributions applied to the biopharmaceutics and developability classification systems.

Eur J Pharm Biopharm 2022 Jan 16;170:160-169. Epub 2021 Dec 16.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom. Electronic address:

After oral administration, a drug's solubility in intestinal fluid is an important parameter influencing bioavailability and if the value is known it can be applied to estimate multiple biopharmaceutical parameters including the solubility limited absorbable dose. Current in vitro measurements may utilise fasted human intestinal fluid (HIF) or simulated intestinal fluid (SIF) to provide an intestinal solubility value. This single point value is limited since its position in relation to the fasted intestinal solubility envelope is unknown. In this study we have applied a nine point fasted equilibrium solubility determination in SIF, based on a multi-dimensional analysis of fasted human intestinal fluid composition, to seven drugs that were previously utilised to investigate the developability classification system (ibuprofen, mefenamic acid, furosemide, dipyridamole, griseofulvin, paracetamol and acyclovir). The resulting fasted equilibrium solubility envelope encompasses literature solubility values in both HIF and SIF indicating that it measures the same solubility space as current approaches with solubility behaviour consistent with previous SIF design of experiment studies. In addition, it identifies that three drugs (griseofulvin, paracetamol and acyclovir) have a very narrow solubility range, a feature that single point solubility approaches would miss. The measured mid-point solubility value is statistically equivalent to the value determined with the original fasted simulated intestinal fluid recipe, further indicating similarity and that existing literature results could be utilised as a direct comparison. Since the multi-dimensional approach covered greater than ninety percent of the variability in fasted intestinal fluid composition, the measured maximum and minimum equilibrium solubility values should represent the extremes of fasted intestinal solubility and provide a range. The seven drugs all display different solubility ranges and behaviours, a result also consistent with previous studies. The dose/solubility ratio for each measurement point can be plotted using the developability classification system to highlight individual drug behaviours. The lowest solubility represents a worst-case scenario which may be useful in risk-based quality by design biopharmaceutical calculations than the mid-point value. The method also permits a dose/solubility ratio frequency distribution determination for the solubility envelope which permits further risk-based refinement, especially where the drug crosses a classification boundary. This novel approach therefore provides greater in vitro detail with respect to possible biopharmaceutical performance in vivo and an improved ability to apply risk-based analysis to biopharmaceutical performance. Further studies will be required to expand the number of drugs measured and link the in vitro measurements to in vivo results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2021.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8769049PMC
January 2022

Insight into the Colonic Disposition of Sulindac in Humans.

J Pharm Sci 2021 01 28;110(1):259-267. Epub 2020 Sep 28.

Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

NSAIDs such as celecoxib and sulindac play a critical role in the treatment of colorectal cancer, yet it is not understood how sufficiently high concentrations are reached in colonic tissue. We previously demonstrated that an incomplete small intestinal absorption of celecoxib enables gut driven drug accumulation in caecal tissue, which is most likely needed for inducing remission. However, a multistage dissolution experiment suggested a more extensive absorption of sulindac relative to celecoxib, though still incomplete. To study whether caecal accumulation of sulindac is solely plasma driven or also gut driven, we performed an exploratory clinical study in healthy volunteers. After intake of a tablet of sulindac (200 mg; Arthrocine), two colonoscopies (1.0-2.5 h, and 6.0-7.5 h after drug intake) were performed to assess concentrations of sulindac and metabolites in plasma, caecal tissue and caecal contents. We observed that sulindac, even without the use of a colon-targeted delivery strategy, can arrive at the colonic lumen due to incomplete absorption and biliary excretion, and that the microbiota can catalyse the production of sulindac sulfide, which then accumulates in a high and local manner in the colonic tissue. These data can be relevant for drug development in the treatment of colorectal adenomas and cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2020.09.034DOI Listing
January 2021

Exploring the Effect of Esomeprazole on Gastric and Duodenal Fluid Volumes and Absorption of Ritonavir.

Pharmaceutics 2020 Jul 17;12(7). Epub 2020 Jul 17.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49-Box 921, 3000 Leuven, Belgium.

Proton-pump inhibitors (PPIs), frequently prescribed to lower gastric acid secretion, often exert an effect on the absorption of co-medicated drug products. A previous study showed decreased plasma levels of the lipophilic drug ritonavir after co-administration with the PPI Nexium (40 mg esomeprazole), even though duodenal concentrations were not affected. The present study explored if a PPI-induced decrease in gastrointestinal (GI) fluid volume might contribute to the reduced absorption of ritonavir. In an exploratory cross-over study, five volunteers were given a Norvir tablet (100 mg ritonavir) orally, once without PPI pre-treatment and once after a three-day pre-treatment with the PPI esomeprazole. Blood samples were collected for eight hours to assess ritonavir absorption and magnetic resonance imaging (MRI) was used to determine the gastric and duodenal fluid volumes during the first three hours after administration of the tablet. The results confirmed that PPI intake reduced ritonavir plasma concentrations by 40%. The gastric residual volume and gastric fluid volume decreased by 41% and 44% respectively, while the duodenal fluid volume was reduced by 33%. These data suggest that the PPI esomeprazole lowers the available fluid volume for dissolution, which may limit the amount of ritonavir that can be absorbed. Although additional factors may play a role, the effect of PPI intake on the GI fluid volume should be considered when simulating the absorption of poorly soluble drugs like ritonavir in real-life conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics12070670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408179PMC
July 2020

Multidimensional analysis of human intestinal fluid composition.

Eur J Pharm Biopharm 2020 Aug 22;153:226-240. Epub 2020 Jun 22.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, United Kingdom. Electronic address:

The oral administration of solid dosage forms is the commonest method to achieve systemic therapy and relies on the drug's solubility in human intestinal fluid (HIF), a key factor that influences bioavailability and biopharmaceutical classification. However, HIF is difficult to obtain and is known to be variable, which has led to the development of a range of simulated intestinal fluid (SIF) systems to determine drug solubility in vitro. In this study we have applied a novel multidimensional approach to analyse and characterise HIF composition using a published data set in both fasted and fed states with a view to refining the existing SIF approaches. The data set provided 152 and 172 measurements of five variables (total bile salt, phospholipid, total free fatty acid, cholesterol and pH) in time-dependent HIF samples from 20 volunteers in the fasted and fed state, respectively. The variable data sets for both fasted state and fed state are complex, do not follow normal distributions but the amphiphilic variable concentrations are correlated. When plotted 2-dimensionally a generally ellipsoid shaped data cloud with a positive slope is revealed with boundaries that enclose published fasted or fed HIF compositions. The data cloud also encloses the majority of fasted state and fed state SIF recipes and illustrates that the structured nature of design of experiment (DoE) approaches does not optimally cover the variable space and may examine media compositions that are not biorelevant. A principal component analysis in either fasted or fed state in combination with fitting an ellipsoid shape to enclose the data results in 8 points that capture over 95% of the compositional variability of HIF. The variable's average rate of concentration change in both fasted state and fed state over a short time scale (10 min) is zero and a Euclidean analysis highlights differences between the fasted and fed states and among individual volunteers. The results indicate that a 9-point DoE (8 + 1 central point) could be applied to investigate drug solubility in vitro and provide statistical solubility limits. In addition, a single point could provide a worst-case solubility measurement to define the lowest biopharmaceutical classification boundary or for use during drug development. This study has provided a novel description of HIF composition. The approach could be expanded in multiple ways by incorporation of further data sets to improve the statistical coverage or to cover specific patient groups (e.g., paediatric). Further development might also be possible to analyse information on the time dependent behaviour of HIF and to guide HIF sampling and analysis protocols.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2020.06.011DOI Listing
August 2020

Insight into the colonic disposition of celecoxib in humans.

Eur J Pharm Sci 2020 Mar 31;145:105242. Epub 2020 Jan 31.

Translational Research Center for Gastrointestinal Disorders, TARGID, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. Electronic address:

Although the effect of NSAIDs such as celecoxib on the progression of colorectal polyps has been established, it is currently unknown how sufficiently high concentrations of celecoxib are reached in colonic tissue. Indeed, the lipophilic and poorly soluble celecoxib is orally dosed as an immediate release capsule without any colon-targeting delivery strategy. In the present study, we aimed to distinguish between plasma and gut driven caecal tissue accumulation of celecoxib in healthy volunteers. After developing a protocol to reliably collect colonic biopsies and contents, the disposition of celecoxib was assessed in plasma, caecal tissue and caecal contents collected after intake of a celecoxib capsule (200 mg; Celebrex®) with 240 mL of tap water. During a first colonoscopy (1.0-2.5 h after drug intake), plasma concentrations of celecoxib and its carboxy metabolite were increasing, while caecal tissue concentrations were relatively low. As no celecoxib was present in caecal contents, tissue accumulation was clearly plasma driven. During a second colonoscopy (6.0-7.5 h after drug intake), tissue concentrations of the drug and its metabolite were substantially higher despite decreasing plasma concentrations. As a high amount of celecoxib was found in the caecal contents, the increased tissue accumulation most likely resulted from direct uptake of celecoxib from the gut. These data demonstrate that incomplete small intestinal absorption of the poorly soluble drug celecoxib enables gut driven drug accumulation in caecal tissue, which is, most likely, critical for the role of this NSAID in the prevention of colorectal cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2020.105242DOI Listing
March 2020

The influence of gastric motility on the intraluminal behavior of fosamprenavir.

Eur J Pharm Sci 2020 Jan 1;142:105117. Epub 2019 Nov 1.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium. Electronic address:

In fasting conditions, the gastrointestinal system contracts according to the interdigestive migrating motor complex (MMC), in which phases of quiescence (MMC phase I) alternate with phases of medium (MMC phase II) to very strong (MMC phase III) contractions. The time of drug intake relative to this cyclic motility pattern may cause variations in formulation behavior. To explore this hypothesis, a cross-over study was performed in healthy volunteers with an immediate release tablet of fosamprenavir (Telzir) which was administered in either MMC phase I or MMC phase II, as determined by high-resolution manometry. In the intestinal tract, fosamprenavir is rapidly hydrolyzed to the active compound amprenavir by alkaline phosphatases. Drug concentrations of both prodrug and drug were determined in the stomach and duodenum and linked to simultaneously assessed systemic concentrations. In 5 out of 6 healthy volunteers, the gastric release of fosamprenavir and the systemic uptake of amprenavir were affected by the MMC phase in which the tablet was administered. The intragastric disintegration of the tablet was faster and less variable after administration in MMC phase II, resulting in faster and less variable uptake of amprenavir in the systemic circulation. Mean plasma t values were 157 (±72.0) and 73.3 (±27.3) min after administration in MMC phase I and MMC phase II, respectively. The study clearly identified the time of oral drug intake relative to the interdigestive motility pattern as a possible source of variation in gastrointestinal drug behavior and absorption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2019.105117DOI Listing
January 2020

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids.

Mol Pharm 2019 12 14;16(12):5042-5053. Epub 2019 Nov 14.

Department of Industrial and Physical Pharmacy, College of Pharmacy , Purdue University , West Lafayette , Indiana 47907 , United States.

Supersaturating formulations are increasingly being used to improve the absorption of orally administered poorly water-soluble drugs. To better predict outcomes in vivo, we must be able to accurately determine the degree of supersaturation in complex media designed to provide a surrogate for the gastrointestinal environment. Herein, we demonstrate that relying on measurements based on consideration of the total dissolved concentration leads to underestimation of supersaturation and consequently membrane transport rates. Crystalline and amorphous solubilities of two compounds, atazanavir and posaconazole, were evaluated in six different media. Concurrently, diffusive flux measurements were performed in a side-by-side diffusion cell to determine the activity-based supersaturation by evaluating membrane transport rates at the crystalline and amorphous solubilities. Solubility values were found to vary in each medium because of different solubilization capacities. Concentration-based supersaturation ratios were also found to vary for the different media. Activity-based measurements, however, were largely independent of the medium, leading to relatively constant values for the estimated supersaturation. These findings have important consequences for modeling and prediction of supersaturation impact on the absorption rate as well as for better defining the thermodynamic driving force for crystallization in complex media.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.9b00956DOI Listing
December 2019

Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems.

Eur J Pharm Sci 2019 Sep 25;137:104967. Epub 2019 Jun 25.

Gattefossé SAS, Saint-Priest, France. Electronic address:

Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2019.104967DOI Listing
September 2019

Co-existing colloidal phases of human duodenal aspirates: Intraindividual fluctuations and interindividual variability in relation to molecular composition.

J Pharm Biomed Anal 2019 Jun 15;170:22-29. Epub 2019 Mar 15.

Drug Transport & Delivery, Dpt. Physics, Chemistry & Pharmacy, University of Southern Denmark, Odense DK-5230, Denmark. Electronic address:

We investigated the ultrastructural pattern of colloidal phases in human duodenal fluids. Aspirates were collected from three volunteers in both fasted and fed nutritional states. Analysis methods comprised the combination of asymmetric flow field-flow fractionation (AF4) and multi-angle laser light scattering (MALLS). Furthermore, dynamic light scattering (DLS) and diffusion-ordered NMR spectroscopy (DOSY-NMR) were employed as alternative analytical approaches for comparison. By AF4/MALLS, up to four, and in some cases up to five distinct co-existing fractions could be differentiated in the sub-micron size-range, which, in accordance with a previous study (Elvang et al., 2018), may be assigned to three main types, namely small bile salt micelles, intermediate size mixed bile salt/phospholipid micelles and large phospholipid aggregates / vesicles. Although more or less the same colloidal phases were found to co-exist in all aspirates, their prevalence was found to vary, both over time and between the three individual human volunteers. Any uniform changes of patterns of colloidal phases over time, however, could not be identified. On the other hand, prevalence of specific colloidal phases was identified for aspirates of individual volunteers, which correlated reasonably well with the prevalence of certain lipid species in their molecular composition. It remains to be investigated whether such prevalence of specific colloidal phases influences drug solubilizing capacity as well as drug absorption. If so, this may help to better understand the substantial inter-individual variability seen in many drug absorption profiles.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpba.2019.03.026DOI Listing
June 2019

In vitro models for the prediction of in vivo performance of oral dosage forms: Recent progress from partnership through the IMI OrBiTo collaboration.

Eur J Pharm Biopharm 2019 Mar 20;136:70-83. Epub 2018 Dec 20.

Drug Delivery and Disposition, KU Leuven, Herestraat 49, Gasthuisberg, O&N2, Box 921, 3000 Leuven, Belgium. Electronic address:

The availability of in vitro tools that are constructed on the basis of a detailed knowledge of key aspects of gastrointestinal (GI) physiology and their impact on formulation performance and subsequent drug release behaviour is fundamental to the success and efficiency of oral drug product development. Over the last six years, the development and optimization of improved, biorelevant in vitro tools has been a cornerstone of the IMI OrBiTo (Oral Biopharmaceutics Tools) project. By bringing together key industry and academic partners, and by linking tool development and optimization to human studies to understand behaviour at the formulation/GI tract interface, the collaboration has enabled innovation, optimization and implementation of the requisite biorelevant in vitro tools. In this paper, we present an overview of the in vitro tools investigated during the collaboration and offer a perspective on their future use in enhancing the development of new oral drug products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.12.010DOI Listing
March 2019

Gastric and Duodenal Diclofenac Concentrations in Healthy Volunteers after Intake of the FDA Standard Meal: In Vivo Observations and in Vitro Explorations.

Mol Pharm 2019 02 9;16(2):573-582. Epub 2019 Jan 9.

KU Leuven Drug Delivery & Disposition , Gasthuisberg O&N2, Herestraat 49 Box 921, 3000 Leuven , Belgium.

This study investigated gastrointestinal drug concentrations of the weakly acidic drug diclofenac when dosed to healthy volunteers after intake of the FDA standard meal. In gastrointestinal aspiration studies, postprandial conditions are usually achieved using liquid or homogenized meals. However, these liquid meals may have a substantially different impact on the gastrointestinal physiology compared to a solid meal. To evaluate the effect of a solid meal on the gastrointestinal behavior of diclofenac, five healthy volunteers were recruited into a clinical study. Twenty minutes prior to diclofenac ingestion (Cataflam, 50 mg of potassium diclofenac), the volunteers were asked to eat a solid meal with the following composition corresponding to the FDA standard meal: 2 eggs, 2 bacon strips, 2 toasts, 4 ounces of hash brown potatoes, and 8 ounces of milk. Gastric and duodenal fluids were collected as a function of time, and blood samples were collected to link the gastrointestinal behavior to systemic exposure. In vivo observations were complemented with in vitro research to obtain a mechanistic understanding of diclofenac's intraluminal behavior. Ingestion of the solid meal resulted in intraluminal pH-profiles similar to earlier studies with a liquid meal. However, intraluminal drug disposition differed. In the stomach, a substantial fraction of diclofenac appeared dissolved, despite an unfavorable acidic pH. Successive in vitro tests suggested that the dissolution of diclofenac is higher in the complex gastric medium resulting from FDA standard meal ingestion compared to liquid meal ingestion. Despite the favorable pH and in contrast to a previous study with a liquid meal, significant amounts of non-dissolved diclofenac were observed in the intestine. Further in vitro tests revealed adsorption of dissolved diclofenac molecules to bacon fragments present in the FDA standard meal. This adsorption negatively affected the permeation of diclofenac across a physical barrier, suggesting that in vivo absorption is affected as well. Being the first time a gastrointestinal aspiration study is combined with the administration of a solid meal, the present study demonstrates that the intraluminal behavior of diclofenac (and possibly other drugs) heavily depends on the consistency and composition of the accompanied meal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.8b00865DOI Listing
February 2019

Exploring gastric drug absorption in fasted and fed state rats.

Int J Pharm 2018 Sep 4;548(1):636-641. Epub 2018 Jul 4.

KU Leuven, Drug Delivery & Disposition, Gasthuisberg O&N2, Herestraat 49 Box 921, 3000 Leuven, Belgium. Electronic address:

The small intestine is generally considered the major site of absorption after oral drug administration. Absorption from the stomach is often disregarded, though passive diffusion across the gastric mucosal barrier is theoretically possible. In this study, an in situ gastric bolus administration model was used to study the gastric absorption of pharmaceutical compounds in fasted and fed state rats. Three drugs [paracetamol (neutral), diclofenac (acidic) and posaconazole (basic)] were administered directly into the stomach as solution (paracetamol and diclofenac) or suspension (posaconazole). Transfer to the intestine was blocked by ligating the pylorus; as a reference, non-ligated conditions were used. Blood samples were collected and gastric absorption was assessed by the appearance of compounds in the systemic circulation. Paracetamol and diclofenac were readily absorbed from the fasted and fed state rat stomach. For paracetamol, the relative contribution of gastric absorption was higher in the fed state compared to the fasted state. Posaconazole absorption was negligible. Since the ability of the stomach to absorb pharmaceutical compounds was clearly confirmed, the present study warrants further research to quantify the contribution of gastric absorption to total gastrointestinal drug absorption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2018.07.017DOI Listing
September 2018

Linking the concentrations of itraconazole and 2-hydroxypropyl-β-cyclodextrin in human intestinal fluids after oral intake of Sporanox.

Eur J Pharm Biopharm 2018 Nov 27;132:231-236. Epub 2018 Jun 27.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - box 921, 3000 Leuven, Belgium. Electronic address:

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman's rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (A-type profile; Spearman's rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.06.025DOI Listing
November 2018

Human intestinal fluid factors affecting intestinal drug permeation in vitro.

Eur J Pharm Sci 2018 08 15;121:338-346. Epub 2018 Jun 15.

KU Leuven, Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. Electronic address:

Intestinal permeability assessment is an important aspect of drug development, which strongly depends on the solvent system used in the intestinal donor compartment. For this purpose, human intestinal fluids (HIF) can be considered as the golden standard. A recent study demonstrated a reduced apparent permeation across rat intestinal tissue from fed versus fasted state HIF for 9 out of 16 compounds tested. Commercially available fed and fasted state simulated fluids (FeSSIF and FaSSIF) reproduced this food effect for only 3 out of 16 compounds. To elucidate this observed difference, the current study assessed the impact of relevant intestinal fluid factors (bile salt, phospholipids, cholesterol, free fatty acids (FFA), monoacylglycerides (MAG)) and 2-factor interactions at a fixed pH of 6.5 on drug permeation across both rat tissue (Ussing chambers setup) and an artificial membrane (dialysis setup). Four representative compounds were selected for the permeation experiments: for propranolol and indomethacin, a food-induced permeation reduction was previously seen in both HIF and SIF; for metoprolol and darunavir, a reduction was only seen in HIF. Using a fractional 2 design of experiments (DoE) approach, 16 SIF combinations were defined as donor media for permeation studies. In the Ussing chambers (rat tissue), FFA and MAG reduced the permeation for all 4 compounds. Only for propranolol and indomethacin, permeation was further reduced by bile salts and phospholipids. This explains why the use of FeSSIF vs FaSSIF, lacking FFA and MAG, predicted a negative food effect for propranolol and indomethacin but not for metoprolol and darunavir. In the dialysis set-up using an artificial membrane, significantly higher permeation rates compared to the Ussing chambers were observed. Under those conditions, FFA and MAG no longer reduced permeation, while bile salts and phospholipids still did. This may indicate that lipidic structures can provide depot release in the case of a dynamic equilibrium between free and entrapped drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2018.06.007DOI Listing
August 2018

Human intestinal fluid layer separation: The effect on colloidal structures & solubility of lipophilic compounds.

Eur J Pharm Biopharm 2018 Aug 24;129:104-110. Epub 2018 May 24.

KU Leuven Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. Electronic address:

In addition to individual intestinal fluid components, colloidal structures are responsible for enhancing the solubility of lipophilic compounds. The present study investigated the link between the ultrastructure of fed state human intestinal fluids (FeHIF) and their solubilizing capacity for lipophilic compounds, taking into account interindividual variability. For this purpose, FeHIF samples from 10 healthy volunteers with known composition and ultrastructure were used to determine the solubility of four lipophilic compounds. In light of the focus on solubility and ultrastructure, the study carefully considered the methodology of solubility determination in relation to colloid composition and solubilizing capacity of FeHIF. To determine the solubilizing capacity of human and simulated intestinal fluids, the samples were saturated with the compound of interest, shaken for 24 h, and centrifuged. When using FeHIF, solubilities were determined in the micellar layer of FeHIF, i.e. after removing the upper (lipid) layer (standard procedure), as well as in total FeHIF (without removal of the upper layer). Compound concentrations were determined using HPLC-UV/fluorescence. To link the solubilizing capacity with the ultrastructure, all human and simulated fluids were imaged using transmission electron microscopy (TEM) before and after centrifugation and top layer (lipid) removal. Comparing the ultrastructure and solubilizing capacity of individual FeHIF samples demonstrated a high intersubject variability in postprandial intestinal conditions. Imaging of FeHIF after removal of the upper layer clearly showed that only micellar structures remain in the lower layer. This observation suggests that larger colloids such as vesicles and lipid droplets are contained in the upper, lipid layer. The solubilizing capacity of most FeHIF samples substantially increased with inclusion of this lipid layer. The relative increase in solubilizing capacity upon inclusion of the lipid layer was most pronounced in samples that contained mainly vesicles alongside the micelles. Current fed state simulated intestinal fluids do not contain the larger colloids observed in the lipid layer of FeHIF and can only simulate the solubilizing capacity of the micellar layer of FeHIF. While the importance of drug molecules solubilized in the micellar layer of postprandial intestinal fluids for absorption has been extensively demonstrated previously, the in-vivo relevance of drug solubilization in the lipid layer is currently unclear. In the dynamic environment of the human gastrointestinal tract, drug initially entrapped in larger postprandial colloids may become available for absorption upon lipid digestion and uptake. The current study, demonstrating the substantial solubilization of lipophilic compounds in the larger colloids of postprandial intestinal fluids, warrants further research in this field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2018.05.026DOI Listing
August 2018

Drug permeability profiling using cell-free permeation tools: Overview and applications.

Eur J Pharm Sci 2018 Jul 13;119:219-233. Epub 2018 Apr 13.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49, Box 921, 3000 Leuven, Belgium. Electronic address:

Cell-free permeation systems are gaining interest in drug discovery and development as tools to obtain a reliable prediction of passive intestinal absorption without the disadvantages associated with cell- or tissue-based permeability profiling. Depending on the composition of the barrier, cell-free permeation systems are classified into two classes including (i) biomimetic barriers which are constructed from (phospho)lipids and (ii) non-biomimetic barriers containing dialysis membranes. This review provides an overview of the currently available cell-free permeation systems including Parallel Artificial Membrane Permeability Assay (PAMPA), Phospholipid Vesicle-based Permeation Assay (PVPA), Permeapad®, and artificial membrane based systems (e.g. the artificial membrane insert system (AMI-system)) in terms of their barrier composition as well as their predictive capacity in relation to well-characterized intestinal permeation systems. Given the potential loss of integrity of cell-based permeation barriers in the presence of food components or pharmaceutical excipients, the superior robustness of cell-free barriers makes them suitable for the combined dissolution/permeation evaluation of formulations. While cell-free permeation systems are mostly applied for exploring intestinal absorption, they can also be used to evaluate non-oral drug delivery by adjusting the composition of the membrane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejps.2018.04.016DOI Listing
July 2018

The artificial membrane insert system as predictive tool for formulation performance evaluation.

Int J Pharm 2018 Feb 12;537(1-2):22-29. Epub 2017 Dec 12.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium. Electronic address:

In view of the increasing interest of pharmaceutical companies for cell- and tissue-free models to implement permeation into formulation testing, this study explored the capability of an artificial membrane insert system (AMI-system) as predictive tool to evaluate the performance of absorption-enabling formulations. Firstly, to explore the usefulness of the AMI-system in supersaturation assessment, permeation was monitored after induction of different degrees of loviride supersaturation. Secondly, to explore the usefulness of the AMI-system in formulation evaluation, a two-stage dissolution test was performed prior to permeation assessment. Different case examples were selected based on the availability of in vivo (intraluminal and systemic) data: (i) a suspension of posaconazole (Noxafil), (ii) a cyclodextrin-based formulation of itraconazole (Sporanox), and (iii) a micronized (Lipanthyl) and nanosized (Lipanthylnano) formulation of fenofibrate. The obtained results demonstrate that the AMI-system is able to capture the impact of loviride supersaturation on permeation. Furthermore, the AMI-system correctly predicted the effects of (i) formulation pH on posaconazole absorption, (ii) dilution on cyclodextrin-based itraconazole absorption, and (iii) food intake on fenofibrate absorption. Based on the applied in vivo/in vitro approach, the AMI-system combined with simple dissolution testing appears to be a time- and cost-effective tool for the early-stage evaluation of absorption-enabling formulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2017.12.025DOI Listing
February 2018

Assessment of Passive Intestinal Permeability Using an Artificial Membrane Insert System.

J Pharm Sci 2018 01 19;107(1):250-256. Epub 2017 Aug 19.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, Leuven 3000, Belgium. Electronic address:

Despite reasonable predictive power of current cell-based and cell-free absorption models for the assessment of intestinal drug permeability, high costs and lengthy preparation steps hamper their use. The use of a simple artificial membrane (without any lipids present) as intestinal barrier substitute would overcome these hurdles. In the present study, a set of 14 poorly water-soluble drugs, dissolved in 2 different media (fasted state simulated/human intestinal fluids [FaSSIF/FaHIF]), were applied to the donor compartment of an artificial membrane insert system (AMI-system) containing a regenerated cellulose membrane. Furthermore, to investigate the predictive capacity of the AMI-system as substitute for the well-established Caco-2 system to assess intestinal permeability, the same set of 14 drugs dissolved in FaHIF were applied to the donor compartment of a Caco-2 system. For 14 drugs, covering a broad range of physicochemical parameters, a reasonable correlation between both absorption systems was observed, characterized by a Pearson correlation coefficient r of 0.95 (FaHIF). Using the AMI-system, an excellent predictive capacity of FaSSIF as surrogate medium for FaHIF was demonstrated (r = 0.96). Based on the acquired data, the AMI-system appears to be a time- and cost-effective tool for the early-stage estimation of passive intestinal permeability for poorly water-soluble drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xphs.2017.08.002DOI Listing
January 2018

In Silico Modeling Approach for the Evaluation of Gastrointestinal Dissolution, Supersaturation, and Precipitation of Posaconazole.

Mol Pharm 2017 12 5;14(12):4321-4333. Epub 2017 Sep 5.

Simcyp Limited (a Certara Company) , Sheffield S2 4SU, United Kingdom.

The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension. A physiologically based pharmacokinetic (PBPK) modeling and simulation tool was applied to simulate GI and systemic concentration-time profiles of posaconazole, which were directly compared with intraluminal and systemic data measured in humans. The Advanced Dissolution Absorption and Metabolism (ADAM) model of the Simcyp Simulator correctly simulated incomplete gastric dissolution and saturated duodenal concentrations of posaconazole in the duodenal fluids following administration of the neutral suspension. In contrast, gastric dissolution was approximately 2-fold higher after administration of the acidified suspension, which resulted in supersaturated concentrations of posaconazole upon transfer to the upper small intestine. The precipitation kinetics of posaconazole were described by two precipitation rate constants, extracted by semimechanistic modeling of a two-stage medium change in vitro dissolution test. The 2-fold difference in exposure in the duodenal compartment for the two formulations corresponded with a 2-fold difference in systemic exposure. This study demonstrated for the first time predictive in silico simulations of GI dissolution, supersaturation, and precipitation for a weakly basic compound in part informed by modeling of in vitro dissolution experiments and validated via clinical measurements in both GI fluids and plasma. Sensitivity analysis with the PBPK model indicated that the critical supersaturation ratio (CSR) and second precipitation rate constant (sPRC) are important parameters of the model. Due to the limitations of the two-stage medium change experiment the CSR was extracted directly from the clinical data. However, in vitro experiments with the BioGIT transfer system performed after completion of the in silico modeling provided an almost identical CSR to the clinical study value; this had no significant impact on the PBPK model predictions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.7b00396DOI Listing
December 2017

Gastric and Duodenal Ethanol Concentrations after Intake of Alcoholic Beverages in Postprandial Conditions.

Mol Pharm 2017 12 11;14(12):4202-4208. Epub 2017 Aug 11.

Drug Delivery & Disposition, KU Leuven , Gasthuisberg O&N2, Herestraat 49 Box 921, 3000 Leuven, Belgium.

This study determined intraluminal ethanol concentrations (stomach and duodenum) in fed healthy volunteers after the consumption of common alcoholic beverages (beer, wine, and whisky). The results of this study were compared with a previous study in fasted volunteers. Five healthy volunteers were recruited in a crossover study. The fed state was simulated by ingestion of 250 mL of Nutridrink Compact Neutral. Volunteers subsequently consumed two standard units of beer (Stella Artois, 500 mL, 5.2% ethanol), wine (Blanc du Blanc, 200 mL, 11% ethanol), or whisky (Gallantry Whisky, 80 mL, 40% ethanol). Gastric and duodenal fluids were aspirated through two catheters over time and analyzed for ethanol content by head space gas chromatography. The capability of ethanol to permeate gastric and duodenal rat mucosa was examined in an Ussing chambers setup. A similar average gastric C was observed in the beer and the wine conditions: 3.3% and 3.7% ethanol, respectively. The gastric C in the whisky condition amounted to 8.5% ethanol. Lower ethanol concentrations were observed in the duodenum compared to the stomach. The duodenal C was similar in all three conditions: 1.3%, 1.2%, and 1.6% ethanol for beer, wine, and whisky, respectively. Compared to the fasted state (reported in a previous study), higher gastric ethanol concentrations were observed during a longer time period. In the beer and wine conditions, similar concentrations were observed in the intestine regardless of the prandial state. After intake of whisky, however, the ethanol concentration was lower in the fed intestine. Alcohol was observed to permeate both gastric and duodenal rat mucosa. Higher intragastric ethanol concentrations were maintained for a longer period of time in fed compared to fasted state conditions. However, the observed concentration profiles were not in line with current FDA guidelines for alcohol resistance testing of formulations, stating that in vitro tests should investigate the impact of up to 40% ethanol for 2 h. The presented intraluminal ethanol concentrations may serve as reference data for the further development of relevant in vitro models to assess ethanol effects on formulation performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.7b00252DOI Listing
December 2017

Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools.

Mol Pharm 2017 12 7;14(12):4220-4232. Epub 2017 Jul 7.

Drug Delivery and Disposition, KU Leuven , Gasthuisberg O&N II, Herestraat 49, Box 921, 3000 Leuven, Belgium.

This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.molpharmaceut.7b00253DOI Listing
December 2017

Gastrointestinal behavior of itraconazole in humans - Part 2: The effect of intraluminal dilution on the performance of a cyclodextrin-based solution.

Int J Pharm 2017 Jun 24;526(1-2):235-243. Epub 2017 Apr 24.

Drug Delivery and Disposition, KU Leuven, Gasthuisberg O&N II, Herestraat 49 - Box 921, 3000 Leuven, Belgium. Electronic address:

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is known to enable absorption of the lipophilic drug itraconazole. Since the interaction between HP-β-CD and itraconazole is characterized by a non-lineair, A-type phase-solubility diagram, the present study aimed to investigate the influence of intraluminal dilution (water intake) on the behavior and performance of an orally administered cyclodextrin-based solution of itraconazole. Subsequently, the in vivo behavior was simulated by combining in vitro dilution with permeation assessment. After the administration of a Sporanox solution to healthy volunteers with or without a glass of water, gastrointestinal and systemic concentrations of itraconazole were simultaneously monitored. Independently of the intake of water, no gastric precipitation of itraconazole was observed. After transfer to the duodenum, precipitation occurred and was more pronounced in the condition with water, resulting in a 7.6-fold reduction in duodenal AUC compared to the condition without water. Nevertheless, plasma concentration-time profiles did not demonstrate any significant differences in AUC, C and t. Application of freshly aspirated intestinal fluids on Caco-2 cells clearly confirmed that higher intestinal itraconazole concentrations after intake of Sporanox without water do not generate a substantially increased itraconazole uptake. A two-stage in vitro dilution test was combined with a permeation compartment to capture this solubility-permeability interplay. In conclusion, this work demonstrates that variations in intraluminal dilution may have a drastic impact on the gastrointestinal behavior of lipophilic drugs in the presence of cyclodextrins. In the case of an AP-type interaction with cyclodextrins, the trade-off between solubility and permeability may be affected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2017.04.057DOI Listing
June 2017
-->