Publications by authors named "Mark McAllister"

53 Publications

Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series.

Pharmaceutics 2022 May 7;14(5). Epub 2022 May 7.

Janssen Research and Development, 2340 Beerse, Belgium.

A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information. Although it was clear from the presentations and Q&A sessions that we continue to make progress in the field of CRDSs and the utility/success of PBBM, there is also a need to continue the momentum and dialogue between the industry and regulators. Five key areas were identified which require further discussion and harmonisation.
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http://dx.doi.org/10.3390/pharmaceutics14051010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9148161PMC
May 2022

infection as an unusual cause of pediatric retinitis: A case report.

Am J Ophthalmol Case Rep 2022 Jun 29;26:101566. Epub 2022 Apr 29.

Department of Ophthalmology & Vision Science, College of Medicine, University of Arizona, 655 N Alvernon Way, Tucson, AZ, 85711, USA.

Purpose: To report a case of infectious pediatric retinitis attributed to Rocky Mountain spotted fever which is rarely reported in the United States.

Observations: A previously healthy 14-year-old male return traveler from Mexico was admitted to the pediatric ICU with septic shock and a diffuse rash. He subsequently complained of blurry vision and was found to have evidence of retinitis on exam. Infectious workup revealed high titers of rickettsial IgM and IgG antibodies. He was treated successfully with 14 days doxycycline and followed up in clinic with improvement in his visual complaints and retinitis.

Conclusions And Importance: Rickettsioses are worldwide endemic zoonotic infections caused by Gram negative obligate intracellular bacteria and spread to humans by infected ticks. Rickettsial infections, including Rocky Mountain spotted fever caused by , are a cause of infectious retinitis, and atypical and zoonotic infections should remain on the differential diagnosis for patients presenting with rash, systemic illness, and visual complaints, even if the patient's travel or exposure history do not immediately suggest a likely rickettsial infection. In general, the ocular manifestations of rickettsial infection improve with systemic doxycycline treatment of the underlying infection.
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http://dx.doi.org/10.1016/j.ajoc.2022.101566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9078999PMC
June 2022

Dissolution Challenges Associated with the Surface pH of Drug Particles: Integration into Mechanistic Oral Absorption Modeling.

AAPS J 2022 01 4;24(1):17. Epub 2022 Jan 4.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA.

The present work aimed to differentiate between in vitro dissolution profiles of ibuprofen as input for GastroPlus™ and to see the impact on systemic exposure. In vitro dissolution profiles of ibuprofen obtained under low- and high-buffered dissolution media were used as input using the z-factor approach. In a second step, a customized surface pH calculator was applied to predict the surface pH of ibuprofen under these low- and high-buffered dissolution conditions. These surface pH values were adopted in GastroPlus™ and simulations were performed to predict the systemic outcome. Simulated data were compared with systemic data of ibuprofen obtained under fasted state conditions in healthy subjects. The slower dissolution rate observed when working under low-buffered conditions nicely matched with the slower dissolution rate as observed during the clinical aspiration study and was in line with the systemic exposure of the drug. Finally, a population simulation was performed to explore the impact of z-factor towards bioequivalence (BE) criteria (so-called safe space). Concerning future perspectives, the customized calculator should be developed in such a way to make it possible to predict the dissolution rate (being informed by the particle size distribution) which, in its turn, can be used as a surrogate to predict the USP2 dissolution curve. Subsequently, validation can be done by using this profile as input for PBPK platforms.
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http://dx.doi.org/10.1208/s12248-021-00663-0DOI Listing
January 2022

In Vitro Simulation of the Environment in the Upper Gastrointestinal Lumen After Drug Administration in the Fed State Using the TIM-1 System and Comparison With Luminal Data in Adults.

J Pharm Sci 2022 01 19;111(1):197-205. Epub 2021 Oct 19.

Department of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece. Electronic address:

We evaluated the environment in TIM-1 luminal compartments using paracetamol and danazol solutions and suspensions and the fed state configuration. Data were compared with recently published data in healthy adults. TIM-1 experiments were performed with a 3-fold downscale. Volumes of secretions in gastric and duodenal compartments adequately reflected the luminal data in adults up to 3 h post drug dosing. pH values in duodenal and jejunal compartments adequately reflected average pH values in adults. In gastric compartment pH values where initially higher than average values in adults and reached baseline levels earlier than in adults. The environment in the TIM-1 gastric compartment and jejunal compartment adequately reflected the average total paracetamol and danazol amounts per volume of contents in the adult stomach and upper small intestine, respectively. Total bile acids concentrations in the micellar phase of contents in duodenal and jejunal compartments overestimated micellar concentrations in the upper small intestine of adults. Adjustments in gastric emptying/acid secretion rates and bile acids identities in the duodenal and jejunal compartments, and application of dynamic bile acids secretion rates are expected to further improve the relevance of luminal conditions in TIM-1 compartments with those in adults.
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http://dx.doi.org/10.1016/j.xphs.2021.10.010DOI Listing
January 2022

X-Linked Retinoschisis and a Coats-Like Response in the Setting of Retinopathy of Prematurity.

J Vitreoretin Dis 2020 Nov 3;4(6):525-529. Epub 2020 Aug 3.

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.

Purpose: This case report describes a unique case of a young patient with retinopathy of prematurity (ROP), a unilateral Coats-like response, and X-linked retinoschisis (XLRS).

Methods: A 9-year-old boy with a history of regressed ROP presented with a unilateral Coats-like response, subretinal exudation, and XLRS. Examination and imaging findings demonstrated a highly unique combination of bilateral retinoschisis and a dramatic unilateral Coats-like response with a large schisis cavity.

Results: Treatment with laser photocoagulation and anti-VEGF therapy led to resolution of the subretinal exudative changes.

Conclusions: This is the first published description to our knowledge of a patient with a Coats-like response, XLRS, and a history of regressed ROP with resolution after treatment.
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http://dx.doi.org/10.1177/2474126420939734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494137PMC
November 2020

Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals.

Pharmaceutics 2021 Mar 20;13(3). Epub 2021 Mar 20.

Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent ME4 4TB, UK.

The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions.
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http://dx.doi.org/10.3390/pharmaceutics13030419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004052PMC
March 2021

Leveraging Oral Drug Development to a Next Level: Impact of the IMI-Funded OrBiTo Project on Patient Healthcare.

Front Med (Lausanne) 2021 5;8:480706. Epub 2021 Mar 5.

Oral Product Development, Pharmaceutical Technology and Development, Operations, AstraZeneca Gothenburg, Mölndal, Sweden.

A thorough understanding of the behavior of drug formulations in the human gastrointestinal (GI) tract is essential when working in the field of oral drug development in a pharmaceutical company. For orally administered drug products, various GI processes, including disintegration of the drug formulation, drugrelease, dissolution, precipitation, degradation, dosage form transit and permeation, dictate absorption into the systemic circulation. These processes are not always fully captured in predictive and tools, as commonly applied in the pre-clinical stage of formulation drug development. A collaborative initiative focused on the science of oral biopharmaceutics was established in 2012 between academic institutions and industrial companies to innovate, optimize and validate these and biopharmaceutical tools. From that perspective, the predictive power of these models can be revised and, if necessary, optimized to improve the accuracy toward predictions of the performance of orally administered drug products in patients. The IMI/EFPIA-funded "Oral Bioavailability Tools (OrBiTo)" project aimed to improve our fundamental understanding of the GI absorption process. The gathered information was integrated into the development of new (or already existing) laboratory tests and computer-based methods in order to deliver more accurate predictions of drug product behavior in a real-life setting. These methods were validated with the use of industrial data. Crucially, the ultimate goal of the project was to set up a scientific framework (i.e., decision trees) to guide the use of these new tools in drug development. The project aimed to facilitate and accelerate the formulation development process and to significantly reduce the need for animal experiments in this area as well as for human clinical studies in the future. With respect to the positive outcome for patients, high-quality oral medicines will be developed where the required dose is well-calculated and consistently provides an optimal clinical effect. In a first step, this manuscript summarizes the setup of the project and how data were collected across the different work packages. In a second step, case studies of how this project contributed to improved knowledge of oral drug delivery which can be used to develop improved products for patients will be illustrated.
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http://dx.doi.org/10.3389/fmed.2021.480706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973356PMC
March 2021

Investigating the Impact of Crohn's Disease on the Bioaccessibility of a Lipid-Based Formulation with an In Vitro Dynamic Gastrointestinal Model.

Mol Pharm 2021 04 3;18(4):1530-1543. Epub 2021 Mar 3.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K.

The aim of the study was to investigate the impact of Crohn's disease (CD) on the performance of a lipid-based formulation of ciprofloxacin in a complex gastrointestinal simulator (TIM-1, TNO) and to compare the luminal environment in terms of bile salt and lipid composition in CD and healthy conditions. CD conditions were simulated in the TIM-1 system with a reduced concentration of porcine pancreatin and porcine bile. The bioaccessibility of ciprofloxacin was similar in simulated CD and healthy conditions considering its extent as well as its time course in the jejunum and ileum filtrate. Differences were observed in terms of the luminal concentration of triglycerides, monoglycerides, and fatty acids in the different TIM-1 compartments, indicating a reduction and delay in the lipolysis of formulation excipients in CD. The quantitative analysis of bile salts revealed higher concentrations for healthy conditions (standard TIM-1 fasted-state protocol) in the duodenum and jejunum TIM-1 compartments compared to published data in human intestinal fluids of healthy subjects. The reduced concentrations of bile salts in simulated CD conditions correspond to the levels observed in human intestinal fluids of healthy subjects in the fasted state.A lipidomics approach with ultra performance liquid chromatography (UPLC)/mass spectrometry (MS) has proven to be a time-efficient method to semiquantitatively analyze differences in fatty acid and bile salt levels between healthy and CD conditions. The dynamic luminal environment in CD and healthy conditions after administration of a lipid-based formulation can be simulated using the TIM-1 system. For ciprofloxacin, an altered luminal lipid composition had no impact on its performance indicating a low risk of altered performance in CD patients.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00807DOI Listing
April 2021

Current challenges and future perspectives in oral absorption research: An opinion of the UNGAP network.

Adv Drug Deliv Rev 2021 04 18;171:289-331. Epub 2021 Feb 18.

College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.

Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
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http://dx.doi.org/10.1016/j.addr.2021.02.001DOI Listing
April 2021

Predicting budesonide performance in healthy subjects and patients with Crohn's disease using biorelevant in vitro dissolution testing and PBPK modeling.

Eur J Pharm Sci 2021 Feb 24;157:105617. Epub 2020 Oct 24.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

Objectives: Drug product performance might be affected in Crohn's disease (CD) patients compared to healthy subjects due to pathophysiological changes. Since a low number of clinical studies is performed in this patient population, physiologically-based pharmacokinetic (PBPK) models with integrated results from biorelevant in vitro dissolution studies could be used to assess differences in the bioavailability of drugs. Using this approach, budesonide was used as model drug and its performance in healthy subjects and CD patients was predicted and compared against observed pharmacokinetic data. The in vitro release tests, under healthy versus CD conditions, revealed a similar extent of drug release from a controlled-release budesonide formulation in the fasted state, whereas in the fed state a lower extent was observed with CD. Differences in the physiology of CD patients were identified in literature and their impact on budesonide performance was investigated with a PBPK model, revealing the highest impact on the simulated bioavailability for the reduced hepatic CYP3A4 enzyme abundance and lower human serum albumin concentration. For CD patients, a higher budesonide exposure compared to healthy subjects was predicted with a PBPK population adapted to CD physiology and in agreement with observed pharmacokinetic data. Budesonide performance in the fasted and fed state was successfully predicted in healthy subjects and CD patients using PBPK modeling and in vitro release testing. Following this approach, predictions of the direction and magnitude of changes in bioavailability due to CD could be made for other drugs and guide prescribers to adjust dosage regimens for CD patients accordingly.
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http://dx.doi.org/10.1016/j.ejps.2020.105617DOI Listing
February 2021

Dissolution testing of modified release products with biorelevant media: An OrBiTo ring study using the USP apparatus III and IV.

Eur J Pharm Biopharm 2020 Nov 31;156:40-49. Epub 2020 Aug 31.

Department of Pharmacy, National and Kapodistrian University of Athens, Zografou, Greece. Electronic address:

During the OrBiTo project, our knowledge on the gastrointestinal environment has improved substantially and biorelevant media composition have been refined. The aim of this study was to propose optimized biorelevant testing conditions for modified release products, to evaluate the reproducibility of the optimized compendial apparatus III (USP apparatus III) and compendial apparatus IV (USP apparatus IV, open-loop mode) dissolution methods and to evaluate the usefulness of these methods to forecast the direction of food effects, if any, based on the results of two «ring» studies and by using two model modified release (MR) products, Ciproxin / Cipro XR and COREG CR. Six OrBiTo partners participated in each of the ring studies. All laboratories were provided with standard protocols, pure drug substance, and dose units. For the USP apparatus III, the dissolution methods applied to Ciproxin / Cipro XR, a monolithic MR product of an active pharmaceutical ingredient (API) with moderate aqueous solubility, were robust with low intra- and inter-laboratory data variability. Data from all partners were in line on a qualitative basis with food effect data in humans. For the USP apparatus IV, the dissolution methods applied to COREG CR, a multiparticulate, pH dependent, MR product of an API with low and pH dependent solubility led to high intra- and inter- laboratory data variability. Data from all partners were in line, on a qualitative basis, with the previously observed food effects in humans.
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http://dx.doi.org/10.1016/j.ejpb.2020.08.025DOI Listing
November 2020

The use of PBPK/PD to establish clinically relevant dissolution specifications for zolpidem immediate release tablets.

Eur J Pharm Sci 2020 Dec 29;155:105534. Epub 2020 Aug 29.

Institute of Pharmaceutical Technology, Goethe University, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Division of Translational Medicine and Pharmacology, Max von Lauer St. 9, Frankfurt am Main, 60438, Germany. Electronic address:

Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (T) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another.

Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant "safe space" for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the "safe space" for dissolution.

Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy.

Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the "safe space" based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem.

Conclusions: A PBPK/PD model indicates that current BCS-biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.
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http://dx.doi.org/10.1016/j.ejps.2020.105534DOI Listing
December 2020

Current status and future opportunities for incorporation of dissolution data in PBPK modeling for pharmaceutical development and regulatory applications: OrBiTo consortium commentary.

Eur J Pharm Biopharm 2020 Oct 8;155:55-68. Epub 2020 Aug 8.

Pharmaceutical Sciences, Merck & Co., Inc., Kenilworth, NJ, USA.

In vitro dissolution experiments are used to qualitatively assess the impact of formulation composition and process changes on the drug dosage form performance. However, the use of dissolution data to quantitatively predict changes in the absorption profile remains limited. Physiologically-based Pharmacokinetic(s) (PBPK) models facilitate incorporation of in vitro dissolution experiments into mechanistic oral absorption models to predict in vivo oral formulation performance, and verify if the drug product dissolution method is biopredictive or clinically relevant. Nevertheless, a standardized approach for using dissolution data within PBPK models does not yet exist and the introduction of dissolution data in PBPK relies on a case by case approach which accommodates from differences in release mechanism and limitations to drug absorption. As part of the Innovative Medicines Initiative (IMI) Oral Biopharmaceutics Tools (OrBiTo) project a cross-work package was set up to gather a realistic understanding of various approaches used and their areas of applications. This paper presents the approaches shared by academic and industrial scientists through the OrBiTo project to integrate dissolution data within PBPK software to improve the prediction accuracy of oral formulations in vivo. Some general recommendations regarding current use and future improvements are also provided.
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http://dx.doi.org/10.1016/j.ejpb.2020.08.005DOI Listing
October 2020

Gastrointestinal diseases and their impact on drug solubility: Crohn's disease.

Eur J Pharm Sci 2020 Sep 7;152:105459. Epub 2020 Jul 7.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

In order to investigate differences in drug solubilisation and dissolution in luminal fluids of Crohn's disease (CD) patients and healthy subjects, biorelevant media representative of CD patients were developed using information from literature and a Design of Experiment (DoE) approach. The CD media were characterised in terms of surface tension, osmolality, dynamic viscosity and buffer capacity and compared to healthy biorelevant media. To identify which drug characteristics are likely to present a high risk of altered drug solubility in CD, the solubility of six drugs was assessed in CD media and solubility differences were related to drug properties. Identified differences in CD patients compared to healthy subjects were a reduced concentration of bile salts, a higher gastric pH and a higher colonic osmolality. Differences in the properties of CD compared to healthy biorelevant media were mainly observed for surface tension and osmolality. Drug solubility of ionisable compounds was altered in gastric CD media compared to healthy biorelevant media. For drugs with moderate to high lipophilicity, a high risk of altered drug solubilisation in CD is expected, since a significant negative effect of log P and a positive effect of bile salts on drug solubility in colonic and fasted state intestinal CD media was observed. Simulating the conditions in CD patients in vitro offers the possibility to identify relevant differences in drug solubilisation without conducting expensive clinical trials.
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http://dx.doi.org/10.1016/j.ejps.2020.105459DOI Listing
September 2020

Gastrointestinal diseases and their impact on drug solubility: Celiac disease.

Eur J Pharm Sci 2020 Sep 6;152:105460. Epub 2020 Jul 6.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

The aim of this study was to develop an in vitro tool for predicting drug solubility and dissolution in intestinal fluids of patients with Celiac disease (CED). Biorelevant media for patients with CED were developed based on published information and a Design of Experiment (DoE) approach. The CED biorelevant media were characterised according to their surface tension, osmolality, dynamic viscosity and buffer capacity. By performing solubility studies of six drugs with different physicochemical properties in CED media, we aimed to identify drugs at high risk of altered luminal solubility in CED patients. Identified differences in CED patients compared to healthy subjects were related to a higher concentration of bile salts, lecithin and cholesterol and included as factors in the DoE resulting in 8 CED biorelevant media. Differences in media properties were observed for the surface tension between biorelevant media based on CED patients and healthy subjects. In terms of solubility, only a minimal effect of CED on the solubility of the hydrophilic neutral compound azathioprine was observed. For neutral moderately lipophilic compounds (budesonide, celecoxib), a higher surfactant concentration resulted in most cases in a higher drug solubility, while it was specific to each drug whether this was mainly driven by bile salts or lecithin. In comparison, drug solubilisation of ionisable compounds with moderate to high lipophilicity was less impacted by CED differences. The developed biorelevant CED media serve as in vitro tool to identify the main media factors impacting on drug solubility.
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http://dx.doi.org/10.1016/j.ejps.2020.105460DOI Listing
September 2020

Gastrointestinal diseases and their impact on drug solubility: Ulcerative Colitis.

Eur J Pharm Sci 2020 Sep 6;152:105458. Epub 2020 Jul 6.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK. Electronic address:

For poorly soluble compounds, drug product performance in patients with Ulcerative Colitis (UC) compared to healthy subjects can be affected due to differences in drug solubility in GI fluids. A risk assessment tool was developed to identify compounds with a high risk of altered solubility in the GI fluids of UC patients. Pathophysiological changes impacting on the composition of GI fluids in UC patients were considered and UC biorelevant media representative of the stomach, intestine and colon were developed based on biorelevant media based on healthy subjects and literature data using a Design of Experiment approach. The UC media were characterised and revealed differences in surface tension, osmolality and buffer capacity compared to media based on healthy subjects. The solubility of six drugs was investigated in UC biorelevant media and results were related to media- and drug-dependent factors. A lower drug solubility in UC intestinal media was observed for compounds with a high lipophilicity. In UC simulated colonic fluids, drug solubility was altered for ionisable compounds. Additionally, a higher solubility of neutral lipophilic drugs was observed in UC fasted state colonic media with increased concentrations of soluble proteins. The developed UC biorelevant media offer the possibility to identify the risk of altered drug solubilisation in UC patients without conducting expensive clinical trials. A high risk was related to drug ionization properties and lipophilicity in the current study with all investigated drugs showing differences in solubility in biorelevant media based on UC patients compared to healthy subjects.
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http://dx.doi.org/10.1016/j.ejps.2020.105458DOI Listing
September 2020

Inorganic fraction of oil sands process-affected water induces mammalian macrophage stress gene expression and acutely modulates immune cell functional markers at both the gene and protein levels.

Toxicol In Vitro 2020 Aug 24;66:104875. Epub 2020 Apr 24.

Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E1, Canada. Electronic address:

The focus of the present study was to examine the acute immunotoxic properties of oil sands process-affected waters (OSPW) using the RAW 264.7 macrophage cell line. Specifically, we used a quantitative PCR assay to monitor changes in the expression of stress, cytokine, and antimicrobial enzyme genes in activated macrophages following acute (i.e. < 24 h) exposure of the cells to whole OSPW and its fractions. Overall, our data shows that OSPW inorganic fraction (IF) significantly induces the expression of genes associated with oxidative stress and DNA damage and that the OSPW-IF also significantly augmented cytokine gene expression. These effects are similar to what was observed following whole OSPW exposures, which contrasts the minimal effects observed when cells were treated with equivalent doses of the OSPW organic fraction (OF). Surprisingly, OSPW-IF had reciprocal effects on gene and protein expression levels of two key macrophage enzymes (e.g. inducible nitric oxide (iNOS) synthase and arginase), which indicates that components within OSPW-IF have the unique ability to alter the overall functional states of macrophage by polarizing them towards an alternatively activated status; concomitant with the reciprocal depression of iNOS levels and enhanced expression and activity of arginase. Collectively, these findings show that at sub-lethal exposure doses, the inorganic constituents of OSPW have significant immunotoxicological properties that could potentially affect innate cellular defense responses of exposed animals.
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http://dx.doi.org/10.1016/j.tiv.2020.104875DOI Listing
August 2020

An interlaboratory investigation of intrinsic dissolution rate determination using surface dissolution.

Eur J Pharm Biopharm 2020 May 14;150:24-32. Epub 2020 Feb 14.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK. Electronic address:

The purpose of this study was to conduct an interlaboratory ring-study, with six partners (academic and industrial), investigating the measurement of intrinsic dissolution rate (IDR) using surface dissolution imaging (SDI) equipment. Measurement of IDR is important in pharmaceutical research as it provides characterising information on drugs and their formulations. This work allowed us to assess the SDI's interlaboratory performance for measuring IDR using a defined standard operating procedure (see supporting information) and six drugs assigned as low (tadalafil, bromocriptine mesylate), medium (carvedilol, indomethacin) and high (ibuprofen, valsartan) solubility compounds. Fasted State Simulated Intestinal Fluid (FaSSIF) and blank FaSSIF (without sodium taurocholate and lecithin) (pH 6.5) were used as media. Using the standardised protocol an IDR value was obtained for all compounds and the results show that the overall IDR rank order matched the solubility rank order. Interlaboratory variability was also examined and it was observed that the variability for lower solubility compounds was higher, coefficient of variation >50%, than for intermediate and high solubility compounds, with the exception of indomethacin in FaSSIF medium. Inter laboratory variability is a useful descriptor for understanding the robustness of the protocol and the system variability. On comparison to another published small-scale IDR study the rank ordering with respect to dissolution rate is identical except for the high solubility compounds. This results indicates that the SDI robustly measures IDR however, no recommendation on the use of one small scale method over the other is made.
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http://dx.doi.org/10.1016/j.ejpb.2020.02.005DOI Listing
May 2020

Developing Clinically Relevant Dissolution Specifications for Oral Drug Products-Industrial and Regulatory Perspectives.

Pharmaceutics 2019 Dec 23;12(1). Epub 2019 Dec 23.

Janssen Research and Development, 2340 Beerse, Belgium.

A meeting that was organized by the Academy of Pharmaceutical Sciences Biopharmaceutics and Regulatory Sciences focus groups focused on the challenges of Developing Clinically Relevant Dissolution Specifications (CRDS) for Oral Drug Products. Industrial Scientists that were involved in product development shared their experiences with in vitro dissolution and in silico modeling approaches to establish clinically relevant dissolution specifications. The regulators shared their perspectives on the acceptability of these different strategies for the development of acceptable specifications. The meeting also reviewed several collaborative initiatives that were relevant to regulatory biopharmaceutics. Following the scientific presentations, a roundtable session provided an opportunity for delegates to discuss the information that was shared during the presentations, debate key questions, and propose strategies to make progress in this critical area of regulatory biopharmaceutics. It was evident from the presentations and subsequent discussions that progress continues to be made with approaches to establish robust CRDS. Further dialogue between industry and regulatory agencies greatly assisted future developments and key areas for focused discussions on CRDS were identified.
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http://dx.doi.org/10.3390/pharmaceutics12010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022466PMC
December 2019

Exploring the enzymatic degradation of poly(glycerol adipate).

Eur J Pharm Biopharm 2019 Sep 15;142:377-386. Epub 2019 Jul 15.

School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom. Electronic address:

Poly(glycerol adipate) (PGA) is a biodegradable, biocompatible, polymer with a great deal of potential in the field of drug delivery. Active drug molecules can be conjugated to the polymer backbone or encapsulated in self-assembled nanoparticles for targeted and systemic delivery. Here, a range of techniques have been used to characterise the enzymatic degradation of PGA extensively for the first time and to provide an indication of the way the polymer will behave and release drug payloads in vivo. Dynamic Light Scattering was used to monitor change in nanoparticle size, indicative of degradation. The release of a fluorescent dye, coupled to PGA, upon incubation with enzymes was measured over a 96 h period as a model of drug release from polymer drug conjugates. The changes to the chemical structure and molecular weight of PGA following enzyme exposure were characterised using FTIR, NMR and GPC. These techniques provided evidence of the biodegradability of PGA, its susceptibility to degradation by a range of enzymes commonly found in the human body and the polymer's potential as a drug delivery platform.
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http://dx.doi.org/10.1016/j.ejpb.2019.07.015DOI Listing
September 2019

Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects.

Eur J Pharm Biopharm 2019 Jun 9;139:101-114. Epub 2019 Mar 9.

Department of Pharmacy, Uppsala University, Uppsala Biomedical Center, P.O. Box 580, SE-75123 Uppsala, Sweden.

Intrinsic dissolution rate (IDR) is the surface specific dissolution rate of a drug. In early drug development, this property (among other parameters) is measured in order to compare different polymorphs and salt forms, guide formulation decisions, and to provide a quality marker of the active pharmaceutical ingredient (API) during production. In this review, an update on different methods and small-scale techniques that have recently evolved for determination of IDR is provided. The importance of biorelevant media and the hydrodynamic conditions of dissolution are also discussed. Different preparation techniques for samples are presented with a focus on disc, particle- and crystal-based methods. A number of small-scale techniques are then described in detail, and their applicability domains are identified. Finally, an updated industrial perspective is provided about IDR's place in the early drug development process.
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http://dx.doi.org/10.1016/j.ejpb.2019.03.011DOI Listing
June 2019

Application of the relationship between pharmacokinetics and pharmacodynamics in drug development and therapeutic equivalence: a PEARRL review.

J Pharm Pharmacol 2019 Apr 22;71(4):699-723. Epub 2019 Feb 22.

Institute of Pharmaceutical Technology, Goethe University, Frankfurt am Main, Germany.

Objectives: The objective of this review was to provide an overview of pharmacokinetic/pharmacodynamic (PK/PD) models, focusing on drug-specific PK/PD models and highlighting their value added in drug development and regulatory decision-making.

Key Findings: Many PK/PD models, with varying degrees of complexity and physiological understanding have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. paediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically based pharmacokinetic and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products.

Summary: Modelling and simulation approaches already play an important role in drug development. While slowly moving away from 'one-size fits all' PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making.
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http://dx.doi.org/10.1111/jphp.13070DOI Listing
April 2019

Trypanosoma carassii infection in goldfish (Carassius auratus L.): changes in the expression of erythropoiesis and anemia regulatory genes.

Parasitol Res 2019 Apr 12;118(4):1147-1158. Epub 2019 Feb 12.

Department of Biological Sciences, CW-405 Biological Sciences Building, University of Alberta, Edmonton, AB, T6G 2E9, Canada.

Trypanosoma carassii is a flagellated bloodstream parasite of cyprinid fish with pathogenesis manifesting primarily as anemia in experimentally infected fish. This anemia is characterized by decreases in the number of circulating red blood cells (RBCs) during peak parasitemia. We examined changes in the key blood metrics and expression of genes known to be important in the regulation of erythropoiesis. Increasing parasitemia was strongly correlated with an overall decrease in the total number of circulating RBCs. Gene expression of key erythropoiesis regulators (EPO, EPOR, GATA1, Lmo2, and HIFα) and proinflammatory cytokines (IFNγ and TNFα) were measured and their expressions differed from those in fish made anemic by injections of phenylhydrazine (PHZ). Significant upregulation of pro-erythropoietic genes was observed in PHZ-induced anemia, but not during peak parasitic infection. Previously, we reported on functional characterization of goldfish erythropoietin (rgEPO) and its ability to induce survival and differentiation of erythroid progenitor cells in vitro. Treatment of goldfish during the infection with rgEPO reduced the severity of anemia but failed to fully prevent the onset of the anemic state in infected fish. Proinflammatory cytokines have been implicated in the suppression of erythropoiesis during trypanosomiasis, specifically the cytokines TNFα, IFNγ, and IL-1β. Analysis of key proinflammatory cytokines revealed that mRNA levels of IFNγ and TNFα were upregulated in response to infection, but only TNFα increased in response to PHZ treatment. Synergistic activity of the proinflammatory cytokines may be required to sustain prolonged anemia. These findings provide insight into the relationship between T. carassii and host anemia and suggest that T. carassii may directly or indirectly suppress host erythropoiesis.
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http://dx.doi.org/10.1007/s00436-019-06246-5DOI Listing
April 2019

Teleost antimicrobial peptide hepcidin contributes to host defense of goldfish (Carassius auratus L.) against Trypanosoma carassii.

Dev Comp Immunol 2019 05 17;94:11-15. Epub 2019 Jan 17.

Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada. Electronic address:

Hepcidin is an antimicrobial peptide and an iron regulatory protein that prevents the release of excess iron in the blood. There is evidence suggesting that teleost hepcidin is a major player in antimicrobial defense against various bacteria species, but little is known regarding the effects of teleost hepcidin in protozoan parasitic infections. We examined the role of hepcidin during the course of infection of goldfish with Trypanosoma carassii. Quantitative real-time PCR was used to determine the expression of hepcidin in goldfish immune organs during the course of T. carassii infection. During the acute phase of the T. carassii infection, the mRNA levels of hepcidin were up-regulated in liver and kidney. In contrast, an up-regulation of hepcidin mRNA expression in spleen was observed during the chronic phase of the infection. Furthermore, a synthetic goldfish hepcidin peptide induced trypanosome lysis in vitro, and parasite surface disruption was confirmed by scanning electron microscopy (SEM) analysis. These results suggest that, in addition to well-characterized direct antibacterial activities, teleost hepcidin also exhibits trypanocidal activity.
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http://dx.doi.org/10.1016/j.dci.2019.01.007DOI Listing
May 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.
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http://dx.doi.org/10.1016/j.ejpb.2018.12.010DOI Listing
March 2019

The impact of food intake on the luminal environment and performance of oral drug products with a view to in vitro and in silico simulations: a PEARRL review.

J Pharm Pharmacol 2019 Apr 11;71(4):557-580. Epub 2018 Sep 11.

Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece.

Objectives: Using the type of meal and dosing conditions suggested by regulatory agencies as a basis, this review has two specific objectives: first, to summarize our understanding on the impact of food intake on luminal environment and drug product performance and second, to summarize the usefulness and limitations of available in vitro and in silico methodologies for the evaluation of drug product performance after food intake.

Key Findings: Characterization of the luminal environment and studies evaluating product performance in the lumen, under conditions suggested by regulatory agencies for simulating the fed state, are limited. Various in vitro methodologies have been proposed for evaluating drug product performance in the fed state, but systematic validation is lacking. Physiologically based pharmacokinetic (PBPK) modelling approaches require the use of in vitro biorelevant data and, to date, have been used primarily for investigating the mechanisms via which an already observed food effect is mediated.

Summary: Better understanding of the impact of changes induced by the meal administration conditions suggested by regulatory agencies on the luminal fate of the drug product is needed. Relevant information will be useful for optimizing the in vitro test methods and increasing the usefulness of PBPK modelling methodologies.
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http://dx.doi.org/10.1111/jphp.12999DOI Listing
April 2019

Impact of gastrointestinal disease states on oral drug absorption - implications for formulation design - a PEARRL review.

J Pharm Pharmacol 2019 Apr 16;71(4):674-698. Epub 2018 May 16.

Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.

Objectives: Drug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed.

Key Findings: Drug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy.

Summary: Development of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential.
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http://dx.doi.org/10.1111/jphp.12928DOI Listing
April 2019

Industry-Academic Collaboration in Oral Biopharmaceutics: The European IMI OrBiTo Project.

Mol Pharm 2017 12;14(12):4129-4131

Sanofi , Bridgewater, New Jersey 08807, United States.

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http://dx.doi.org/10.1021/acs.molpharmaceut.7b00940DOI Listing
December 2017

Factors Influencing Oral Anticoagulant Prescribing Practices for Atrial Fibrillation.

J Stroke 2017 May 2;19(2):232-235. Epub 2017 May 2.

Division of Stroke and Cerebrovascular Diseases, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, USA.

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http://dx.doi.org/10.5853/jos.2016.01102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466293PMC
May 2017

Biopharmaceutics data management system for anonymised data sharing and curation: First application with orbito IMI project.

Comput Methods Programs Biomed 2017 Mar 18;140:29-44. Epub 2016 Nov 18.

AstraZeneca Global Operations, Pharmaceutical Technology and Development Silk Road Business Park, Charter Way, Macclesfield, SK10 2NA, England.

The OrBiTo IMI project was designed to improve the understanding and modelling of how drugs are absorbed. To achieve this 13 pharmaceutical companies agreed to share biopharmaceutics drug properties and performance data, as long as they were able to hide certain aspects of their dataset if required. This data was then used in simulations to test how three in silico Physiological Based Pharmacokinetic (PBPK) tools performed. A unique database system was designed and implemented to store the drug data. The database system was unique, in that it had the ability to make different sections of a dataset visible or hidden depending on the stage of the project. Users were also given the option to hide identifying API attributes, to help prevent identification of project members from previously published data. This was achieved by applying blinding strategies to data parameters and the adoption of a unique numbering system. An anonymous communication tool was proposed to exchange comments about data, which enabled its curation and evolution. This paper describes the strategy adopted for numbering and blinding of the data, the tools developed to gather and search data as well as the tools used for communicating around the data with the aim of publicising the approach for other pre-competitive research between organisations.
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http://dx.doi.org/10.1016/j.cmpb.2016.11.006DOI Listing
March 2017
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