Pharmacy - Doctoral Theses

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Antimicrobial stewardship in Ireland, with a focus on long term care facilities
(University College Cork, 2015) Fleming, Aoife; Byrne, Stephen; Health Research Board
Background: Antimicrobial resistance is a major public health concern, and its increasing incidence in the Long Term Care Facility (LTCF) setting warrants attention (1). The prescribing of antimicrobials in this setting is often inappropriate and higher in Ireland than the European average (2). The aim of the study was to generate an evidence base for the factors influencing antimicrobial prescribing in LTCFs and to investigate Antimicrobial Stewardship (AMS) strategies for LTCFs. Methods: An initial qualitative study was conducted to determine the factors influencing antimicrobial prescribing in Irish LTCFs. This allowed for the informed implementation of an AMS feasibility study in LTCFs in the greater Cork region. Hospital AMS was also investigated by means of a national survey. A study of LTCF urine sample antimicrobial resistance rates was conducted in order to collate information for incorporation into future LTCF AMS initiatives. Results: The qualitative interviews determined that there are a multitude of factors, unique to the LTCF setting, which influence antimicrobial prescribing. There was a positive response from the doctors and nurses involved in the feasibility study as they welcomed the opportunity to engage with AMS and audit and feedback activities. While the results did not indicate a significant change in antimicrobial prescribing over the study period, important trends and patterns of use were detected. The antimicrobial susceptibility of LTCF urine samples compared to GPs samples found that there was a higher level of antimicrobial resistance in LTCFs. Conclusion: This study has made an important contribution to the development of AMS in LTCFs. The complexity of care and healthcare organisation, and the factors unique to LTCFs must be borne in mind when developing quality improvement strategies.
Application of mesoporous silica for the oral delivery of poorly water-soluble drugs
(University College Cork, 2014) Ahern, Robert J.; Crean, Abina M.; Ryan, Katie B.; Science Foundation Ireland
The objective of this thesis was to improve the dissolution rate of the poorly waters-soluble drug, fenofibrate by processing it with a high surface area carrier, mesoporous silica. The subsequent properties of the drug – silica composite were studied in terms of drug distribution within the silica matrix, solid state and release properties. Prior to commencing any experimental work, the properties of unprocessed mesoporous silica and fenofibrate were characterised (chapter 3), this allowed for comparison with the processed samples studied in later chapters. Fenofibrate was a highly stable, crystalline drug that did not adsorb moisture, even under long term accelerated storage conditions. It maintained its crystallinity even after SC-CO2 processing. Its dissolution rate was limited and dependent on the characteristics of the particular in vitro media studied. Mesoporous silica had a large surface area and mesopore volume and readily picked up moisture when stored under long term accelerated storage conditions (75% RH, 40 oC). It maintained its mesopore character after SC-CO2 processing. A variety of methods were employed to process fenofibrate with mesoporous silica including physical mixing, melt method, solvent impregnation and novel methods such as liquid and supercritical carbon dioxide (SC-CO2) (chapter 4). It was found that it was important to break down the fenofibrate particulate structure to a molecular state to enable drug molecules enter into the silica mesopores. While all processing methods led to some increase in fenofibrate release properties; the impregnation, liquid and SC-CO2 methods produced the most rapid release rates. SC-CO2 processing was further studied with a view to optimising the processing parameters to achieve the highest drug-loading efficiency possible (chapter 5). In this thesis, it was that SC-CO2 processing pressure had a bearing on drug-loading efficiency. Neither pressure, duration or depressurisation rate affected drug solid state or release properties. The amount of drug that could be loaded onto to the mesoporous silica successfully was also investigated at different ratios of drug mass to silica surface area under constant SC-CO2 conditions; as the drug – silica ratio increased, the drug-loading efficiency decreased, while there was no effect on drug solid state or release properties. The influence of the number of drug-loading steps was investigated (chapter 6) with a view to increasing the drug-loading efficiency. This multiple step approach did not yield an increase in drug-loading efficiency compared to the single step approach. It was also an objective in this chapter to understand how much drug could be loaded into silica mesopores; a method based on the known volume of the mesopores and true density of drug was investigated. However, this approach led to serious repercussions in terms of the subsequent solid state nature of the drug and its release performance; there was significant drug crystallinity and reduced release extent. The impact of in vitro release media on fenofibrate release was also studied (chapter 6). Here it was seen that media containing HCl led to reduced drug release over time compared to equivalent media not containing HCl. The key findings of this thesis are discussed in chapter 7 and included: 1. Drug – silica processing method strongly influenced drug distribution within the silica matrix, drug solid state and release. 2. The silica surface area and mesopore volume also influenced how much drug could be loaded. It was shown that SC-CO2 processing variables such as processing pressure (13.79 – 41.37 MPa), duration time (4 – 24 h) and depressurisation rate (rapid or controlled) did not influence the drug distribution within the SBA- 15 matrix, drug solid state form or release. Possible avenues of research to be considered going forward include the development and application of high resolution imaging techniques to visualise drug molecules within the silica mesopores. Also, the issues surrounding SBA-15 usage in a pharmaceutical manufacturing environment should be addressed.
Application of pharmaceutical quality approaches and the development of process analytical technologies to improve pharmaceutical product and process understanding
(University College Cork, 2020-09-29) Queiroz, Ana Luiza P.; Crean, Abina; Vucen, Sonja; Science Foundation Ireland; European Regional Development Fund
The pharmaceutical industry is undergoing a paradigm change with the advancement towards the Fourth Industrial Revolution. The manufacturing framework is moving from batch to continuous, which has been accompanied by the necessity of the implementation of process analytical technologies (PAT) for continuous process monitoring and control. There has also been a need to develop advanced quality approaches such as Quality by Design (QbD) and Quality by Control (QbC). Within these quality approaches, modelling has been used to expand knowledge related to raw material attributes and transformations that happen during the process, and to monitor and control process parameters. Besides the development of models for process and product transformations understanding and monitoring, predictive models have been an important advancement to reduce experimental cost during formulation development and process design. There are challenges that need to be addressed in order to complete the implementation of continuous process and advanced quality approaches in that pharmaceutical sector. It is necessary to extend the full mechanistic knowledge of processes, to develop data analysis and computer simulation, to expand the number of equipment and models to scale up solutions, and to upskill personnel to work with the technologies required. The general aim of this thesis was to increase understanding of pharmaceutical materials and processes by the development of PAT and models for quantitative characterization and prediction of drug substance and drug product critical properties. To achieve this aim, several specific objectives were established focused on different aspects of oral dosage form manufacture. Initially, a PAT was developed to rapidly characterize microcrystalline cellulose (MCC) percentage crystallinity index. MCC crystallinity was determined from Raman spectral data. Then, MCC moisture sorption and moisture monolayer were determined from isotherms obtained using dynamic vapor sorption (DVS). A correlation between both attributes was investigated. However, it was not possible to confirm the relationship between the monolayer moisture sorption and the percentage crystallinity. A total of 30 commercial batches of MCC were used to design and validate the MCC crystallinity model. Furthermore, a web application, McCrystal, was designed to disseminate the model. Available at https://sspc.ie/mccrystal/. Secondly, a PAT was developed to determine the endpoint and monitor form changes during slurry co-crystallization. This PAT tool involved the application of in situ Raman spectroscopy combined with principal component analysis (PCA). An additional PAT tool was developed using Mid Infrared spectroscopy (MIRS) combined with multivariate curve resolution (MCR) in order to quantitatively evaluate phase purity of co-crystals produced by slow evaporation and slurry co-crystallization. The models developed were applied to different combinations of active pharmaceutical ingredients (APIs) and coformers, and were able to determine the co-crystallization endpoint for all systems where the solvents exhibited a weak Raman signal. Moreover, the phase purity for all co-crystals systems investigated was determined. The third challenge addressed by this study relates to particle-particle interactions in powder blends to predict the general behaviour of the blend when it is directly compressed into pharmaceutical tablets. Percolation threshold model was used to determine a critical drug load, above which the powder blend behaves similarly to the drug substance. As a result, the formulation may show undesirable properties above the threshold, which can lead to non-compliance or process difficulties. The application of PCA to determine the critical drug loading was investigated. The predicted values of critical drug loading were confirmed by changes in powder flowability, tablet weight variation, and Raman spectroscopic analysis of drug distribution. PCA was not able to precisely predict the threshold, however, it aided in clarifying differences between the blends containing different ibuprofen loadings and different MCC grades. Expanding on the impact of critical drug loading on tablet critical quality attributes, the final objective was to investigate the impact of critical drug loads, determined from compaction data, on disintegration and dissolution performance. The application of novel process analytical technologies, in-process video microscopy (PVM) and focused-beam reflectance measurement (FBRM), to study tablet disintegration was also proposed and investigated in-depth. FBRM and PVM provided important information of tablet disintegration behaviour that cannot be captured by the traditional disintegration testing. The critical drug load predicted from compaction data was also relevant for disintegration and dissolution behaviour. Above the threshold drug loading, disintegration and drug release rates were decreased. A PCA model developed from Raman spectra acquired from tablet surfaces further supported the finding that blends manufactured with different grades of MCC differed more significantly above the critical drug load. The work presented in this thesis is a contribution to solid dosage formulation design, co-crystallization understanding, tableting process scale up and scale down, and data handling. The models and PAT developed can be used to predict formulation performance, determine process parameters based on raw material critical attributes, determine process endpoint, and thoroughly assess final product critical quality attributes.
Computational pharmaceutics approaches to inform drug developability: focus on lipid-based formulations
(University College Cork, 2021-10-04) Bennett-Lenane, Harriet; Griffin, Brendan T.; O'Shea, Joseph; O'Driscoll, Caitriona M.; Irish Research Council
Purpose: Declining productivity in the face of increasing numbers of poorly water-soluble drugs has fast-tracked necessity for predictive tools which assess the delivery potential of bio-enabling formulations. However, there is a perceived risk associated with early-stage selection of bio-enabling formulations. Computational pharmaceutics is a growing area of research interest to support structured guidance in formulation strategy. Using data-driven modelling, a streamlined roadmap of computational possibilities for development scientists is possible. Accordingly, the aim of this thesis was to examine the application of machine learning (ML) computational modelling to inform candidate developability. Via prediction of both quality target product profile characteristics and formulation performance indicators for lipid-based formulations (LBF). In recognition of the fact that computational models will not entirely circumvent need for manual screening, a further aim was to explore if analysis of landrace pig gastrointestinal fluids could facilitate increased bio-predictive performance of in vitro tools for LBFs. Methods: Data-driven computational models using various ML algorithms, with both classification and regression outputs, were developed to predict food effect on bioavailability, solubility ratio (SR) upon self-emulsifying drug delivery system (SEDDS) dispersion and apparent degree of supersaturation (aDS) ratio in supersaturated LBFs (sLBF). Model performance was validated using test sets or comparisons to ex vivo results. Gastrointestinal fluids from the landrace pig were collected in the fasted state, fed state and post placebo SEDDS administration. Ex vivo solubility analysis and microscopic imaging were completed using these fluids, where in vitro biorelevant dispersion screening with SEDDS using various dilution conditions was compared to the ex vivo results. Results: Firstly, this thesis demonstrated the applicability of ML for the prediction of a quality target product profile characteristic of interest in early development, namely food effect on bioavailability. Secondly, this thesis has advanced computational pharmaceutics to inform drug developability. Computational predictions of solubility gain upon SEDDS dispersion informed a biopharmaceutical dose number in intestinal fluids, which can be incorporated within the developability classification system (DCS) framework to inform drug developability. Thirdly, in recognition of the use of supersaturated LBFs to overcome dose loading limitations, this thesis has demonstrated how ML algorithms can predict the maximum dose loading upon thermal induced supersaturation. Moreover, increased understanding of the fate of SEDDS upon oral administration furthered the utility of the pig pre-clinical model, validated accuracy of in silico predictions and aided development of a bio-predictive in vitro screening tool for LBFs. Ultimately, it was demonstrated that the computational and in vitro tools developed in this thesis can be embedded within a wider refined drug substance to drug product development framework. Conclusion: This thesis highlighted how pharmaceutics datasets are amenable to ML. The ability of computational pharmaceutics to facilitate structured formulation decisions was demonstrated. As model development aided increased understanding of the investigated phenomena through their relationship to drug properties, this thesis identified the significant potential to be gained from early analysis of drug properties. Additionally, utility of the landrace pig model to inform increasingly bio-predictive in vitro screening tools was established. The proposed refining of the drug substance to drug product development framework demonstrated the significance of both computationally informed and experimentally confirmed aspects of drug developability decision-making.
Design and development of supersaturated lipid-based drug delivery systems for applications in pharmaceutical industry
(University College Cork, 2020-07-04) Ilie, Alexandra-Roxana; Griffin, Brendan T.; Holm, René; Horizon 2020
Purpose: The need to administer high doses of poorly water-soluble drugs in preclinical studies has guided pharmaceutical research towards evaluation of supersaturated lipid-based drug delivery systems (sLBDDS). Design and development of sLBDDS in a pharmaceutical industry setting was the main purpose of this thesis. Methods: The model drugs (celecoxib, cinnarizine, JNJ-2A) and a set of LBDDS based on excipients with different properties were investigated in solubility studies, in vitro dispersion tests and in vitro static or dynamic dispersion/digestion-permeation studies. In vivo behaviour of drugs after administration as LBDDS and/or sLBDDS was evaluated using developed plasma drug quantification methods Results: Firstly, the supersaturation propensity in eight LBDDS was shown to be different for the model drugs. High apparent supersaturation degrees (aDS) were obtained for celecoxib and cinnarizine, while low aDS were found for JNJ-2A Secondly, systematic investigation of lipid excipient influence on in vivo performance of LBDDS showed that simple one or two-component LBDDS have a positive effect on drug absorption relative to three-component systems containing triglycerides. Additionally, a statistically significantly higher drug absorption in case of celecoxib and cinnarizine was seen for some long chain (LC) compared to medium chain (MC) LBDDS. Furthermore, it was indicated that a simplified test using assembled pre- and post-digestive biorelevant media consisting of dispersed or digested lipid excipients can help screen drug solubilization and further inform choice of LC or MC lipid excipients in candidate formulations, while dispersion and dilution testing correlated well with in vivo findings. Thirdly, thermally-induced drug supersaturation in one-component LBDDS resulted in higher celecoxib bioavailability relative to LBDDS, yet the drug supersaturation effect did not result in higher drug permeation in in vitro dispersion/digestion-permeation studies under static or dynamic conditions. Nevertheless, the positive effect of LC LBDDS seen in vivo was also identified in the developed in vitro models. Finally, a negative effect of thermally-induced supersaturation was observed for the precipitation-prone drug, cinnarizine. Nevertheless, cinnarizine absorption was improved by inclusion of precipitation inhibitors (PI) in the formulation, albeit only statistically significant for one sLBDDS-PI. Conclusions: Thermally-induced supersaturation resulted in increased celecoxib bioavailability from sLBDDS relative to LBDDS consisting of mono- and di-glycerides as single lipid excipient. Compositional effects were seen both in in vivo studies and in vitro dispersion/digestion-permeation testing for celecoxib. For cinnarizine, an inherent precipitation risk from sLBDDS was observed independent of lipid system composition. In contrast to celecoxib, thermally-induced supersaturation resulted in lower drug absorption relative to LBDDS, yet a positive influence was observed after inclusion of PIs in the formulations. For JNJ-2A, modest aDS were obtained using the tested lipid systems and only a minor influence of lipid composition was observed in vivo. This thesis showed that sLBDDS can be used for poorly-water soluble drugs as means to increase drug loadings and could be potentially used in preclinical studies to maximise in vivo exposure. Formulation development guidance tools are provided at the end of this thesis to aid scientists in designing and developing sLBDDS.
Design and evaluation of novel microencapsulation technologies to enhance delivery of Ciclosporin
(University College Cork, 2014) Keohane, Kieran; Griffin, Brendan T.; Science Foundation Ireland
Drug delivery systems influence the various processes of release, absorption, distribution and elimination of drug. Conventional delivery methods administer drug through the mouth, the skin, transmucosal areas, inhalation or injection. However, one of the current challenges is the lack of effective and targeted oral drug administration. Development of sophisticated strategies, such as micro- and nanotechnology that can integrate the design and synthesis of drug delivery systems in a one-step, scalable process is fundamental in advancing the limitations of conventional processing techniques. Thus, the objective of this thesis is to evaluate novel microencapsulation technologies in the production of size-specific and target-specific drug-loaded particles. The first part of this thesis describes the utility of PDMS and silicon microfluidic flow focusing devices (MFFDs) to produce PLGA-based microparticles. The formation of uniform droplets was dependent on the surface of PDMS remaining hydrophilic. However, the durability of PDMS was limited to no more than 1 hour before wetting of the microchannel walls with dichloromethane and subsequent swelling occurred. Critically, silicon MFFDs revealed very good solvent compatibility and was sufficiently robust to withstand elevated fluid flow rates. Silicon MFFDs facilitated experiments to run over days with continuous use and re-use of the device with a narrower microparticle size distribution, relative to conventional production techniques. The second part of this thesis demonstrates an alternative microencapsulation technology, SmPill® minispheres, to target CsA delivery to the colon. Characterisation of CsA release in vitro and in vivo was performed. By modulating the ethylcellulose:pectin coating thickness, release of CsA in-vivo was more effectively controlled compared to current commercial CsA formulations and demonstrated a linear in-vitro in-vivo relationship. Coated minispheres were shown to limit CsA release in the upper small intestine and enhance localised CsA delivery to the colon.
Development of a dissolvable microneedle influenza vaccine patch
(University College Cork, 2016) Allen, Evin A.; Crean, Abina; Moore, Anne; College of Medicine and Health, University College Cork
Delivery of large molecular weight biological molecules to the epidermis and dermis is constrained by the tough outer layer of the epidermis, the stratum corneum (sc). Microneedle technologies attempt to overcome this physical barrier using sharp micron-size projections to penetrate the sc. Dissolvable microneedles (DMN), are a particular microneedle design whereby the needle structure is composed of a soluble matrix that upon application to the skin, dissolves releasing the vaccine load into skin. This thesis examines (1) the formulation and processing considerations around DMN fabrication, (2) the immunogenicity of DMN containing trivalent influenza vaccine (TIV) in pre-clinical mouse and pig models and (3) the thermostability of these DMN formulations during storage. The results demonstrate the importance of formulation for microneedle formation and mechanical strength. Trehalose and polyvinylalcohol based formulations produced optimal microneedle structures and were amenable to piezoelectric dispensing; allowing for precise multi-layered DMN to be fabricated. The effect of drying conditions was assessed and found to be critical for DMN mechanical strength and skin penetration. The antibody responses to TIV generated by DMN-mediated vaccination were comparable or greater to those induced by immunization with a commercial TIV via the IM route in mice. DMN mediated immunisation resulted in a significantly broader humoral response to heterotypic influenza viruses compared to IM delivery. Stored at 40°C, a licensed seasonal influenza vaccine incorporated into DMN array was thermostable for at least 6 month as determined by Single Radial Immunodiffusion and immunogenicity in mice. The thesis advances the field of DMN influenza vaccination by elucidating important processing and formulation considerations in the fabrication of highly reproducible DMN. It also demonstrated that DMN can induce broader, larger humoral responses than conventional IM administration while demonstrating enhanced accelerated stability. Crucially, this works advances an automated fabrication system that will allow for clinical translation of DMN.
Drug dissolution from mesoporous silica systems
(University College Cork, 2018) McCarthy, Carol A.; Crean, Abina; European Regional Development Fund; Science Foundation Ireland
Mesoporous silica materials have been investigated as novel formulation aids for oral drug delivery due to their drug solubility enhancing characteristics. However, the mechanism of drug release from these systems is not well understood. Several studies have reported unexplained incomplete release from mesoporous silica carriers. It has been reported, in other research fields, that passive drug adsorption onto the silica surface is possible. However, the implications for this behaviour on drug release from silica systems has not been considered to date. Dissolution studies involving these formulations are generally conducted using Type II dissolution apparatus under sink conditions with traditional simple buffer media. In this thesis, the suitability of this dissolution approach for mesoporous silica systems is considered. The overall aim of this thesis was to investigate factors influencing drug adsorption and release from mesoporous silica systems to enhance understanding of their drug release profiles. This thesis began with a comprehensive overview of the literature which identified the gaps in knowledge in this area. Based on these findings, the hypothesis, aims and objectives were developed. The four research chapters were each dedicated to factors which could potentially affect drug release; formulation excipients, dissolution medium, drug/silica interactions and dissolution apparatus. The role of drug adsorption on the silica surface was explored across several of the chapters using adsorption isotherms, adsorption models and spectroscopic techniques. Several aspects of dissolution experimental design were investigated including sink and supersaturating conditions, traditional simple buffer media versus biorelevant media and Type II (paddle) apparatus versus Type IV (flow-through cell) and a Transfer model (incorporating an SGF to FaSSIF-V2 media transfer). Finally, the results of in vitro dissolution studies were compared to in vivo performance in a fasting pig model. The literature review demonstrated the gap in knowledge concerning the mechanism of drug release from mesoporous silica systems. This informed the central themes of the thesis which were explored in four research chapters. In Chapter 3, it was determined that formulation excipients which can reduce surface tension of the dissolution media (e.g. surfactants) can significantly increase drug release from mesoporous silica carriers. Passive drug adsorption and competitive adsorption involving drug and surfactant molecules on the silica surface was also observed. Chapter 4 built on work from the previous chapter and demonstrated that components of biorelevant media that reduced surface tension can also enhance drug release from silica systems. This chapter established that the influence of biorelevant media extends beyond its impact on drug supersaturation promotion and that its use should also be recommended under sink conditions. In Chapter 5, the focus was placed on investigating drug/silica interactions under supersaturating conditions. It was determined these interactions occur through a hydrogen bonding process and not via non-specific hydrophobic interactions. It was determined that the dynamic equilibrium which exists between adsorbed and free drug during passive adsorption and dissolution can be related to the drug’s activity in solution. Finally, in Chapter 6, it was observed that dissolution experimental design can influence in vitro drug release from mesoporous silica systems. It was established that the Type IV apparatus incorporating an SGF -> FaSSIF-V2 transfer is the best predictor of in vivo performance. The findings of this thesis have made a significant contribution to enhancing knowledge on drug release from mesoporous silica systems. It provides robust recommendations for the design of in vitro dissolution studies involving mesoporous silica formulations including choice of dissolution media, drug supersaturation level and dissolution apparatus. Interesting results concerning the influence of drug activity in solution on the equilibrium process observed during drug adsorption and dissolution from mesoporous silica materials were documented. These findings open up interesting new avenues for future research in the field of mesoporous silica carriers for oral drug delivery.
Economic evaluations of clinical pharmacy services in Ireland, 2007-2015
(University College Cork, 2016) Gallagher, James; Byrne, Stephen; Mccarthy, Suzanne; Woods, Noel; Eustace, Joe; Health Research Board
Introduction The concept of this thesis was driven by stagnation within the Irish healthcare system. Multiple reports from pharmacy organisations had outlined possible future directions for the profession but progress was minimal, especially in comparison with other countries. The author’s directive was to evaluate the economic impact of a series of clinical pharmacy services (CPS) in hospital and community settings. Methods A systematic review of economic evaluations of clinical pharmacy services in hospital patients was undertaken to gain insight into recent research in the field. Eligible studies were evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS), to establish the quality, consistency and transparency of relevant research. A retrospective analysis of an internal hospital pharmacy interventions database was conducted. A method first described by Nesbit et al. was implemented to estimate the level of cost avoidance achieved. A cost-effectiveness analysis based on data from a randomised controlled trial of a pharmacist-supervised patient self-testing (PST) of warfarin therapy is presented. Outcome measure was the incremental cost associated with six months of intervention management. A similar cost-effectiveness analysis based on previously published RCT data was used to evaluate a novel structured pharmacist review of medication in older hospitalised patients. Cost-effectiveness analysis was presented in the form of an incremental cost-effectiveness ratio (ICER). An ICER is an additional cost per unit effect, in the case of this study, the cost of preventing an additional non-trivial ADR in hospital. A method described by Preaud et al. was adapted to estimate the clinical and economic benefit gained from vaccination of patients by a community pharmacist in Ireland in 2013/14. Sample demographic data was obtained from a national chain of community pharmacies and applied to overall national vaccination data. Results Systematic review identified twenty studies which were eligible for inclusion. Overall, pharmacist interventions had a positive impact on hospital budgets. Only three studies (15%) were deemed to be “good-quality” studies. No ‘novel’ clinical pharmacist intervention was identified during the course of this review. Analysis of internal hospital database identified 4,257 interventions documented on 2,147 individual patients over a 12 month period. Substantial cost avoidance of €710,000 was generated over a 1 year period from the perspective of the health care provider. Mean cost avoidance of €166 per intervention was generated. The cost of providing these interventions was €82,000. Substantial net cost-benefits of €626,279 and a cost-benefit ratio of 8.64 : 1 were generated based on this evaluation of pharmacist interventions. Results from an evaluation of a novel pharmacist-led form of warfarin management indicated indicated that on a per patient basis, PST was slightly more expensive than established anticoagulant management. On a per patient basis over a six month period, PST resulted in an incremental cost of €59.08 in comparison with routine care. Overall cost of managing a patient through pharmacist-supervised PST for a six month period is €226.45. However, for this increase in cost a clinically significant improvement in care was provided. Patients achieved a significantly higher time in therapeutic range during the PST arm in comparison with routine care, (72 ± 19.7% vs 59 ± 13.5%). Difference in overall cost was minimal and PST was the dominant strategy in some scenarios examined during sensitivity analysis. Structured pharmacist review of medication was determined to be dominant in comparison to usual pharmaceutical care. Even if the healthcare payer was unwilling to pay any money for the prevention of an ADR, the intervention strategy is still likely to be cost-effective (probability of being determined cost-effective = 0.707). Implementation of pharmacist-led influenza vaccination has resulted in substantial clinical and economic benefits to the healthcare system. The majority of patients (64.9%) who availed of this service had identifiable influenza-related risk factors. Of patients with influenza-related risk factors, age ≥65 year was the most commonly cited risk factor. Pharmacist vaccination services averted a total of 848 influenza cases across all age groups during the 2013/2014 influenza season. Due to receipt of vaccination in a pharmacy setting, 444 influenza-related GP visits were prevented. In terms of more serious influenza-associated events, 11 hospitalisations and five influenza-related deaths were averted. Costs averted were approximately €305,000. These were principally wider societal-related costs associated with lost productivity. Conclusion Overall, clinical pharmacy services are adding value to the Irish healthcare system in both hospital and community settings, but provision of additional funding for new services would enable them to offer a great deal more.
An exploration of deprescribing barriers and facilitators for older patients in primary care in Ireland – the potential role of the pharmacist
(University College Cork, 2019) Hansen, Christina Raae; Byrne, Stephen; O'Mahony, Denis; Kearney, Patricia M.; Sahm, Laura
Introduction: The older population, often defined as people aged ≥ 65 years is growing. With older age, the risk of multimorbidity (commonly defined as the presence of ≥ 2 chronic conditions) increases together with the use of a high number of daily medicines or polypharmacy (≥ 5 daily medicines). These are two risk factors of poor health outcomes in older people, putting them at greater risk of experiencing potentially inappropriate prescribing (PIP), adverse drug events (ADEs) and poor quality of life (QoL). To reduce polypharmacy and the associated risk, the number of medications used per patient needs to be reduced by means of carefully considered deprescribing when appropriate. Deprescribing is the process of discontinuing inappropriate medications with the goal of optimising pharmacotherapy and improving health outcomes. Existing research is limited to support the effective and practical implementation of deprescribing. Pharmacists are trained to evaluate PIP and their knowledge and skills may benefit the process of deprescribing. As the majority of prescribing takes place in primary care, it is logical that GPs would liaise with community pharmacists in a collaborative intervention/practice to deprescribe. Therefore, the aim of this thesis was to identify the challenges and potential benefits of deprescribing, and to explore the potential involvement of the community pharmacist in deprescribing. Methods: A study design comprising both quantitative and qualitative designs was used. Firstly, a narrative literature review summarised the existing qualitative and quantitative literature on healthcare professionals’ views on deprescribing (Chapter 2). Secondly, a systematic literature review and meta-analysis was conducted according to the PRISMA guidelines, to determine the effectiveness of existing deprescribing interventions (Chapter 3). Thirdly, to determine if PIP is predominantly a phenomenon of later life or whether it has its origins in early old age, a secondary data analysis of a population-based primary care cohort of patients aged 60-74 years was done over a continuous five-year period (Chapter 4). Fourthly, total net ingredient cost (NIC) was estimated for the PIMs identified in the same population-based primary care cohort studied in Chapter 4 in the period from 2016 to 2018, and a potential cost reduction of the routine application of the STOPP criteria was determined (Chapter 5). Fifthly, the views of community pharmacists on their role in medication optimisation and reducing PIP was examined in a qualitative interview study (Chapter 6). Finally, the views of general practitioners (GPs) and community pharmacists, on their collaboration and the potential role of the pharmacist in deprescribing, were explored in a qualitative study (Chapter 7). Results: The narrative review (Chapter 2) included 23 studies. The content analysis identified five broad themes describing the barriers and facilitators of deprescribing in older patients with multimorbidity: (i) interprofessional relationships, (ii) medication review, (iii) information, (iv) the patient and (v) environmental needs. The systematic literature review (Chapter 3) summarised findings of 31 studies of which 30 studies were included in the behaviour change component (BCT) analysis and 21 were included in the meta-analysis. The meta-analysis showed that deprescribing interventions are effective in reducing the number of drugs and inappropriate prescribing in older people, although the evidence is mixed. BCT clusters more frequently present in studies reporting intervention effectiveness compared to studies reporting no effectiveness were: goals and planning; shaping knowledge; natural consequences; comparison of behaviour; comparison of outcomes; regulation; antecedents; and identity. A total of 974 participants aged 60-74 years were included in the secondary analysis in Chapter 4 and data from baseline to year 5 of follow-up was studied. The odds of being exposed to potential prescribing omissions (PPOs) and potentially inappropriate medications (PIMs) increased significantly during years of follow-up (OR 1.08, 95% CI 1.07 1.09 and OR 1.04 95% CI 1.03, 1.06, respectively). A higher number of medicines and new diagnoses were associated with the increasing trend in both PPO and PIM prevalence. The cost-analysis in Chapter 5 was based on the same population studied in Chapter 4 (n=974) but in the period from 2016 to 2018 (year 6 to year 8 of follow-up). The study showed a high prevalence of PIMs (46%-52%) during the study period. The total net ingredient cost of PIMs identified ranged from €87,152.04 at year 6 and €86,112.48 at year 8 of follow-up. The mean cost of PIM per participant per year was between €178.68 - €179.64 during the three years of follow-up. The qualitative interviews (Chapter 6) included a total 18 community pharmacists. Seven domains from theoretical domains framework (TDF) were identified as relevant to PIP reduction and pharmacist involvement: (i) beliefs about capabilities, (ii) environmental context and resources, (iii) knowledge, (iv) social influences, (v) social professional role and identity, (vi) memory, attention and decision processes, and (vii) reinforcement. In Chapter 7, a total of 26 interviews were conducted with GPs and community pharmacists. The thematic content analysis identified five themes relevant to the role of the community pharmacist in deprescribing: (i) the GP’s role in deprescribing – is there room for a pharmacist?, (ii) working relationship, (iii) the role of the pharmacist in deprescribing, (iv) patients’ interaction with the healthcare system, and (v) environmental factors. Conclusions: The findings presented in this thesis provide a detailed understanding of the potential role of the community pharmacist in deprescribing. The prospective benefits of and the barriers and facilitators to pharmacists involved in this role of deprescribing have also been elucidated. This thesis contributes to the existing literature, through the provision of novel research that demonstrates the need for the community pharmacist support within the context of deprescribing. The community pharmacist is in a favourable position to bring pharmaceutical care closer to the patient through patient counselling and close collaboration with the patient’s GP. To integrate the role of the pharmacist with that of the GP in practice, there is a need to consider the mode of pharmaceutical service delivery and to expand the collaboration between community pharmacists and GPs by building on existing positive experiences of collaboration and clearly define the role and responsibilities of the community pharmacist in deprescribing.
Exploring the utility of lipid-based formulation technology to enhance oral bioavailability of BCS class IV molecules
(University College Cork, 2020-04-30) Koehl, Niklas J.; Griffin, Brendan T.; Holm, Rene; Kuentz, Martin; Horizon 2020
Purpose: Increasing numbers of poorly water-soluble drugs emerging from discovery pipelines have led to formulation delivery challenges. Poorly water-soluble drugs that exhibit limited in vivo bioavailability generate a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. While traditionally, highly lipophilic drugs (i.e. ‘grease ball’ drugs) were considered to be suitable candidates for a LBF approach, to date few studies have attempted to explore the biopharmaceutical benefits of LBFs for ‘brick dust’ drug candidates due to excessive hydrophobicity which tends to lead to insufficient solubility in lipid excipients and dose loading limitations in LBF solutions. Therefore, the increasing pool of hydrophobic and lipophilic drug candidates emerging from discovery are traditionally not considered for a LBF approach. This creates a need for advanced LBF types to address the dose loading limitations and potentially unleash the additional lipid mediated effects for enhancing oral absorption such as increased post-digestive intestinal solubilisation, increased permeability and promotion of lymphatic transport. While there are a range of advanced LBFs available, studies to date have mostly been demonstrated with model drugs that no longer truly reflect the emerging drug discovery space and hence the applicability of these alternative LBF approaches to the current ‘brick dust’ pipeline drugs is unknown. The aim of this thesis was to explore the utility of advanced LBFs to overcome solubility limited oral absorption of poorly water-soluble ‘brick dust’ drugs, as well as the establishment of an industrial developability guide for LBF development for hydrophobic, lipophilic and high molecular weight drugs. Methods: The suitability of LBF suspensions, supersaturated LBF solutions (sLBF), LBF solutions using lipophilic salts and the chase dosing approach for current pipeline drugs was evaluated using the model ‘brick dust’ drugs nilotinib and venetoclax. In addition, the incorporation of precipitation inhibitors (PIs) into sLBFs was investigated. The formulations were assessed in vitro using the standard pH stat lipolysis setup as well as quick screening tools such as simulated post-digestive media or a solvent shift based supersaturation/precipitation assay. All tested formulations were subsequently evaluated in vivo either in rats or landrace pigs. Subsequently, based on the findings in these studies and current literature a LBF development guide was proposed. Results: This thesis has firstly demonstrated that while surfactant suspensions increased the bioavailability, poorly dispersible oil-only suspensions should be avoided, as it may lead to particle entrapment in the lipid vehicle. It was further shown that the concomitant administration (chase dosing) of the ‘brick dust’ drug, nilotinib, with LBF excipients increased the bioavailability in rats and was able to overcome the limitations of the poorly dispersible oily suspension approach. Thirdly it was demonstrated that highly digestible surfactants resulted in a higher bioavailability of nilotinib relative to low or non-digested surfactants using surfactant-only suspensions. Furthermore, it was shown that a thermally induced supersaturation approach achieved a higher drug loading in oily lipid excipients, which facilitated the use of sLBFs in pre-clinical in vivo studies. Subsequently, it was demonstrated that sLBFs increased the bioavailability of venetoclax in vivo. In addition, it was demonstrated that the use of PIs in such supersaturated lipid systems did not increase the bioavailability but rather showed a decreased bioavailability. Moreover, the thesis showed that a thermodynamically stable LBF solution, which was obtained via synthesis of lipophilic salts of venetoclax, increased the bioavailability significantly relative to the commercialised solid dispersion. The combined lipophilic salt-LBF solution achieved a bioavailability similar to the commercial solid dispersion in the fed state. Ultimately, the thesis also demonstrated that standard in vitro testing was useful in identifying LBF potential and in explaining observed formulation performance in vivo. However, the employed in vitro tools were not in all cases predictive of the in vivo situation, generating the need for more, fast and high throughput tools for these advanced LBF formulation approaches. Conclusion: This thesis demonstrated the utility of LBFs for drugs displaying both poor water and lipid solubility and therefore exhibit dose loading limitations in conventional lipid vehicles. A bioavailability increase was achieved with all LBF approaches, showing that dose limitations in a lipid vehicle due to excessive hydrophobicity do not preclude a LBF approach. However, it was also demonstrated that care should be taken in terms of the excipient choice and existing biopharmaceutical knowledge should be integrated to achieve the most effective LBF. A Lipid Formulation Developability Guide (LFDG) was proposed to provide industrial guidance on the development of LBFs for such drug candidates. Overall, the impact of this thesis is that the range of application for LBFs can be extended to include difficult to formulate ‘brick dust’ molecule throughout the development process.
Exploring the utility of the pig model for predicting bioavailability in humans
(University College Cork, 2020-07-01) Henze, Laura J.; Griffin, Brendan T.; Holm, René; Vertzoni, Maria; Horizon 2020
Purpose It has been increasingly recognised that there is a need to reduce costly drug development delays and facilitate earlier access to market for new medicines. Within drug development, there is considerable debate on which preclinical animal model is most appropriate for assessing oral bioavailability in humans. In order to streamline preclinical development, and reduce repeated testing in various animal models, it is necessary to get a better understanding which particular animal model is suitable for a specific drug candidate. In pharmaceutical drug development, preclinical tests in animal models are essential to demonstrate whether the new drug is orally bioavailable and to gain a first insight into in vivo pharmacokinetics (PK) parameters that can subsequently be used to predict human values. Preclinical testing, therefore, provides essential scientific evidence in advance of pivotal clinical testing in humans on the safety and efficacy of new drug candidate. Despite significant advances in development of bio-predictive in vitro models and increasing ethical expectations for reducing the number of animals used for research purposes, there is still a need for appropriately selected preclinical in vivo testing to provide guidance on the decision to progress to testing in humans. The selection of appropriate animal models is essential both to maximise the learning that can be obtained from such experiments and to avoid unnecessary testing in a range of species. Selection of the right species for the various questions and compounds is therefore a critical step. While there has been extensive discussion in the literature on the use of dog and non-human primate models to predict oral bioavailability in humans (Musther et al., 2014), in relation to the pig model there are significant gaps in our understanding. Methods The suitability of the pig as a preclinical model within pharmaceutical research was evaluated using bioenabling formulations of the model drugs fenofibrate and venetoclax. In addition, the ability of predicting food dependent bioavailability was assessed for both compounds. The formulations were evaluated in vivo in landrace (LR) pigs. Followed by a post-mortem assessment of the gastrointestinal (GI) fluids, to assess fasted and fed study protocols. Subsequently the physiological composition of the porcine GI fluids has been characterised in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. Based on the findings a porcine biorelevant media (FaSSIFp) was proposed. Porcine GI transit conditions were studied with a telemetric motility capsule (SmartPill®) under fasted and postprandial conditions, by determining pH values, pressure and temperature. The physiological GI knowledge of pigs has been combined in a pig specific absorption model, to predict drug levels prospectively. Results This thesis has firstly demonstrated the suitability of the pig as a preclinical model for predicting oral bioavailability in humans. Moreover, it was the first report in the literature, where the pig model was used successfully capturing clinical reported food dependent bioavailability of the two model drugs fenofibrate and venetoclax. It was further shown that established study protocols, achieved fasted state conditions in pigs. Secondly a porcine biorelevant medium was proposed and has shown the advantage to predict luminal solubility in pigs more accurately in comparison to human biorelevant media. Thirdly an improved porcine physiologically based absorption model was used to prospectively simulate the impact of food on the bioavailability of venetoclax. By using porcine biorelevant media in combination with an in silico pig specific absorption model, it was possible to correctly predict the observed pig plasma concentration profile and food effect. Conclusion The thesis demonstrated that pigs are a suitable model in preclinical research to predict drug product performance and oral bioavailability in humans, including challenging compounds and different formulation strategies. The established porcine physiologically based pharmacokinetic (PBPK) model in combination with the proposed porcine biorelevant medium, can lead to more efficient preclinical processes and provide for more informed decision making on the formulation properties, as summarized in a species specific development guide. Establishing reliable and appropriate in vitro models to reflect preclinical conditions, can lead to reduction and replacement of animal experiments in preclinical development processes. Overall, the impact of this thesis is that the range of application of the pig model can be extended, to address parallel goals in in vivo animal studies, by evaluating optimal formulation strategies to improve drug absorption, as well as predicting impact of food on oral drug product performance early in the product lifecycle.
Exploring vaccine decision-making to identify and address barriers to vaccine uptake in Ireland
(University College Cork, 2020-04-05) Marshall, Sarah; Sahm, Laura; Moore, Anne; Fleming, Aoife; Naji Foundation
Introduction: Vaccination is one of the greatest public health achievements of the last century. However, vaccine uptake rates worldwide remain sub-optimal. The vaccine decision-making process is complex and multifaceted and multiple barriers to vaccine uptake have already been identified. However, these barriers are highly variable and context specific. Therefore, there is an urgent need to identify and address the factors contributing to decreasing vaccine uptake in Ireland. Aim: The aim of this doctoral research was to explore vaccine decision-making in order to identify, and address, barriers to vaccine uptake in Ireland. Methods: Multiple approaches were used to address this aim. A comprehensive literature review, and subsequent qualitative research, involving parents sought to understand if and how microneedle technology could impact vaccine decision-making and vaccine uptake. In addition, a systematic review and meta-ethnographic synthesis of the qualitative literature and a series of qualitative studies, involving both adolescents and parents, sought to gain an insight into the HPV vaccine decision-making process, to identify barriers to vaccine uptake. This culminated in the development and evaluation of a theory and evidence-based intervention, involving parent-daughter dyads. Results: The vaccine decision-making process was explored qualitatively, in a series of studies, involving multiple stakeholders. Factors such as perception of disease risk, trust in healthcare system, and to a lesser extent, knowledge, interact to impact vaccine decision-making, in the midst of variable, yet omnipresent vaccine safety concerns. Conclusion: This thesis has provided a comprehensive overview of vaccine decision-making and has identified the barriers to vaccine uptake perceived by key stakeholders. These identified barriers may be addressed by policy-makers and vaccinators, to enhance vaccine uptake in Ireland.
Factors affecting prescriber implementation of medication appropriateness recommendations in hospitalised older adults
(University College Cork, 2019) Dalton, Kieran; Byrne, Stephen; O'Mahony, Denis; Seventh Framework Programme
Introduction: Despite the well-documented association between potentially inappropriate prescribing (PIP) and adverse outcomes for hospitalised older adults, the prevalence of PIP remains unacceptably high. Recommendations to improve medication appropriateness in hospital often come from sources external to the attending prescribing team, such as pharmacists and computerised system alerts. However, these recommendations to minimise PIP are not always implemented by prescribers, meaning that PIP can continue, thereby increasing the risk of adverse drug reactions (ADRs), rehospitalisation, and higher healthcare costs. Interventions with sufficiently high rates of adherence to medication appropriateness recommendations among prescribers are more likely to result in significantly improved patient outcomes in comparison to those interventions with lower implementation rates, which often show non-significant effects on key outcomes. Thus, it is imperative that prescribing optimisation interventions achieve sufficiently high prescriber implementation rates for these recommendations to be clinically effective. However, it is not always clear which specific intervention components are essential to high implementation rates of prescribing recommendations. Therefore, the overarching aim of this thesis was to identify the key factors affecting prescriber implementation of recommendations to improve medication appropriateness in hospitalised older adults, focusing on the factors affecting implementation of i) computer-generated recommendations and ii) pharmacist recommendations. Methods: Initially, a systematic review and meta-analysis were undertaken to ascertain the effectiveness of computerised interventions in minimising PIP in hospitalised older adults. Secondly, a semi-structured qualitative interview study was conducted alongside the Software ENgine for the Assessment & optimization of drug and non-drug Therapy in Older peRsons (SENATOR) trial to determine the key factors affecting prescriber implementation of the SENATOR software-generated recommendations, which aimed to reduce PIP and ADRs in hospitalised older adults. Based on these qualitative findings, an evaluation of the clinical relevance of SENATOR’s computer-generated recommendations based on Screening Tool of Older People's Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START) criteria (version 2) was performed. Subsequently, the association between the clinical relevance of the recommendations and their implementation by prescribers was assessed. Thereafter, the prescriber implementation rates of STOPP/START recommendations from a physician approach and a pharmacist approach were compared. Finally, a further semi-structured qualitative interview study was conducted to identify the key factors affecting physician prescriber implementation of pharmacist recommendations aimed at optimising medication appropriateness in hospitalised older adults. Results: The systematic review and meta-analysis showed that computerised interventions can significantly reduce PIP in hospitalised older adults (p < 0.05). Of the nine included studies, five reported prescriber implementation rates for the computer-generated recommendations, ranging from 22.5% – 95%, but none of the included studies comprehensively explored the underlying reasons for non-implementation. The qualitative study conducted alongside the SENATOR trial identified four key factors affecting prescriber implementation of the computer-generated recommendations: i) Computerised output: the clinical relevance and method of provision for the recommendations. ii) Acute hospital environment: the timing and location of recommendations in a busy and often pressurised clinical setting. iii) Prescriber role and identity: the responsibility, experience, and specialty of prescribers, as well as their attitude towards research studies. iv) Patient-specific details: knowing the patient, patient preferences, and their acutely ill status in hospital. The study evaluating the clinical relevance of the computer-generated SENATOR recommendations showed that nearly three quarters of the 925 computer-generated STOPP/START recommendations generated were judged to be clinically relevant (73.6%), whilst the remainder were judged to be of ‘no clinical relevance’ (21.5%) or of potential ‘adverse significance’ if implemented (4.9%). Recommendations judged to be of higher clinical relevance were significantly more likely to be implemented than those of lower clinical relevance (p < 0.05), substantiating the findings from the preceding qualitative study that clinical relevance was a key factor affecting implementation. In the study comparing the implementation of pharmacist-provided and physician-provided STOPP/START recommendations, prescribers implemented a significantly greater proportion of physician recommendations in comparison to pharmacist recommendations (83.4% versus 37.8%; p < 0.0001). The final qualitative interview study found that the key factors affecting prescriber implementation of pharmacists' medication appropriateness recommendations for hospitalised older adults were: i) Clinical relevance and complexity of the recommendation. ii) Interprofessional communication. iii) Prescriber role and identity. iv) Knowing each other and developing trusting relationships. v) Hospital environment. Conclusion: This thesis has made a significant contribution to the understanding of the key factors affecting prescriber implementation of recommendations to improve medication appropriateness in hospitalised older adults. Prescriber non-implementation of these recommendations is not attributable to one easily identifiable cause, and it is likely that a multi-faceted approach will be required in future interventions. The novel studies conducted in this thesis will facilitate the development of theoretically-informed interventions that result in enhanced prescriber implementation of these recommendations, ultimately with the aims of substantially reducing PIP and improving health outcomes for hospitalised older adults.
Gene delivery for the treatment of prostate cancer
(University College Cork, 2016) Fitzgerald, Kathleen A.; O'Driscoll, Caitriona M.; Irish Cancer Society
Prostate cancer is one of the most common cancers diagnosed in men. Whilst treatments for early-stage disease are largely effective, current therapies for metastatic prostate cancer, particularly for bone metastasis, offer only a few months increased lifespan at best. Hence new treatments are urgently required. Small interfering RNA (siRNA) has been investigated for the treatment of prostate cancer where it can ‘silence’ specific cancer-related genes. However the clinical application of siRNA-based gene therapy is limited due to the absence of an optimised gene delivery vector. The optimisation of such gene delivery vectors is routinely undertaken in vitro using 2D cell culture on plastic dishes which does not accurately simulate the in vivo bone cancer metastasis microenvironment. The goal of this thesis was to assess the potential of two different targeted delivery vectors (gold or modified β-cyclodextrin derivatives) to facilitate siRNA receptor-mediated uptake into prostate cancer cells. Furthermore, this project aimed to develop a more physiologically relevant 3D in vitro cell culture model, to mimic prostate cancer bone metastasis, which is suitable for evaluating the delivery of nanoparticulate gene therapeutics. In the first instance, cationic derivatives of gold and β-cyclodextrin were synthesized to complex anionic siRNA. The delivery vectors were targeted to prostate cancer cells using the anisamide ligand which has high affinity for the sigma receptor that is overexpressed by prostate cancer cells. The gold nanoparticle demonstrated high levels of uptake into prostate cancer PC3 cells and efficient gene silencing when transfection was performed in serum-free media. However, due to the absence of a poly(ethylene glycol) (PEG) stabilising group, the formulation was unsuitable for use in serum-containing conditions. Conversely, the modified β-cyclodextrin formulation demonstrated enhanced stability in the presence of serum due to the inclusion of a PEG chain onto which the anisamide ligand was conjugated. However, the maximum level of gene silencing efficacy from three different prostate cancer cell lines (DU145, VCaP and PC3 cells) was 30 %, suggesting that further optimisation of the formulation would be required prior to application in vivo. In order to develop a more physiologically-relevant in vitro model of prostate cancer bone metastasis, prostate cancer cells (PC3 and LNCaP cells) were cultured in 3D on collagenbased scaffolds engineered to mimic the bone microenvironment. While the model was suitable for assessing nanoparticle-mediated gene knockdown, prostate cancer cells demonstrated a phenotype with lower invasive potential when grown on the scaffolds relative to standard 2D cell culture. Hence, prostate cancer cells (PC3 and LNCaP cells) were subsequently co-cultured with bone osteoblast cells (hFOB 1.19 cells) to enhance the physiological relevance of the model. Co-cultures secreted elevated levels of the MMP9 enzyme, a marker of prostate cancer metastasis, relative to prostate cancer cell monocultures (2D and 3D) indicating enhanced physiological relevance of the model. Furthermore, the coculture model proved suitable for investigating nanoparticle-mediated gene silencing. In conclusion, the work outlined in this thesis identified two different sigma receptor-targeted gene delivery vectors with potential for the treatment of prostate cancer. In addition, a more physiologically relevant model of prostate cancer bone metastasis was developed with the capacity to help optimise gene delivery vectors for the treatment of prostate cancer.
Ghrelin system signalling in appetite and reward: in vitro and in vivo perspectives
(University College Cork, 2018) Howick, Kenneth P.; Griffin, Brendan T.; Schellekens, Harriët; FHI 360
The regulation of food intake is one of the most intricate internal balances in mammalian behaviour. Dysregulation of the central mechanisms underlying appetite control and metabolism result in both disorders of under- and over-eating. Disorders of appetite result in significant morbidity and mortality, and represent a major unmet clinical need. The endogenous hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR-1a), have long been known as pharmacological targets for appetite-related and metabolic disorders. Nutraceutical and bioactive peptides offer the opportunity to prevent onset and escalation of lifestyle-associated diseases of appetite and metabolism. However, there is a dearth of clinical evidence to justify the development of many bioactives as nutraceuticals. The potential applicability of dairy-derived bioactives in appetite-related disorders is now becoming increasingly apparent. We investigate whether a dairy-derived hydrolysate can increase GHSR-1a signalling in vitro, and whether this can be translated to evidence of effect in vivo in a pre-clinical model (Chapter 2). Subsequently, by leveraging advanced pharmaceutical technology, we develop a gastro-protective and sustained delivery system with a high payload capacity (Chapter 3). Furthermore, ligand-dependent biased signalling, and ligand biodistribution may have important roles to play in increasing efficacy of ghrelin ligands in vivo. Therefore, we investigate whether two synthetic ghrelin ligands, anamorelin and HM01, exert differential effects on the GHSR-1a in vitro (Chapter 4). The divergent effects of these two ligands on appetite and reward-motivated behaviours, as well as effects on central neuronal activation and reward system dopamine (DA) levels will also be investigated with a view to informing strategies to optimize future ghrelin therapies (Chapter 4 and 5). Chapter 2 and 3 provide an effective platform for gastro-protected delivery of bioactive peptides to enable further proof-of-concept studies across the appetite modulation field. Evidence of an orexigenic effect of the bioactive is seen in vivo in a rodent model. The oral delivery system developed served as a clinical formulation platform for proof-of-concept studies in humans to be conducted within the wider Food for Health Ireland research consortium. Chapters 4 and 5 show the importance of biased signalling and biodistribution of ghrelin ligands. Greater maximal food intake is reported by the brain penetrant HM01 vs. the peripherally limited anamorelin. Divergent neuronal activation of the two ligands is also shown in reward processing areas using c-fos immunostaining. Targeting specific downstream signalling pathways will enable the provision of more efficacious appetite modulation therapies, while centrally penetrant ligands will provide further therapeutic avenues through greater reward system activation.
Guideline-led prescribing to heart failure patients in Ireland and Egypt
(University College Cork, 2019-06) El Hadidi, Seif; Bermingham, Margaret; Byrne, Stephen; Darweesh, Ebtissam; Future University in Egypt; University College Cork
Introduction: Guidelines strongly recommend patients with Heart Failure (HF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Guideline-led prescribing of HF evidence-based medicines is strongly associated with improved survival, prognosis, and quality of life in HF. The guidelines strongly recommend, and the optimal patient outcomes are achieved with an appropriate prescription of target doses of all HF therapies. The degree to which gaps in medication use and dosing persist in contemporary Irish or Egyptian practices is unclear. Aim: To assess guideline-led prescribing of the evidence-based HF medications in routine clinical practice in Ireland and Egypt and to assess the prevalence of HF-specific potentially inappropriate prescribing in the same Irish and Egyptian clinical settings. Method: Firstly, a narrative literature review was undertaken to determine and compare the available data and gaps in knowledge regarding HF management in Ireland as a developed European country, and Egypt as a developing Middle-Eastern country, with a particular focus on the guideline-directed medical therapies. Secondly, a systematic review was undertaken to identify the objective quantitative tools to assess the quality of HF prescribing practice. Next, a prospective cohort study was conducted on an Irish outpatient population to evaluate the extent of use and dosing of the guideline-directed medical therapies. Then, a multicentre retrospective study was carried out in 14 Long-Term Care (LTC) facilities in Cork County to assess the prevalence of appropriate and potentially inappropriate prescribing practices. In Egypt, a longitudinal observational study was conducted in order to evaluate the prescribing quality and patterns in HF patients in an Egyptian critical care setting at discharge. Finally, a descriptive survey was developed to address the barriers to guideline-led prescribing in a middle-income setting. Results: The literature review identified many gaps in knowledge in the Egyptian and Irish literature on HF. For instance, the studies included in the review did not discuss the target dose prescribing. The systematic review identified the widespread use of the Guideline Adherence Index (GAI-3) in 13 studies worldwide in the quantitative assessment of HF prescribing. The Irish HF outpatient study showed room for optimising the prescription of the guideline-directed medical therapies in 34% of ambulatory patients. No patient achieved the 100% target dose of all three evidence-based medications. The prevalence of potentially inappropriate prescribing was 20%. The Irish LTC study showed that patients with HF were older than those without HF (84.8 ± 7.4 vs 83.4 ± 7.9 years, p-value = 0.024). Loop diuretic was the most frequently prescribed HF medication up to 88% of the total population and renin-angiotensin system inhibitors to 24.2% only. The prevalence of potentially inappropriate prescribing in LTC was 24%. On the other hand, the Egyptian longitudinal study showed the moderate adherence level at discharge from the critical care unit but the potential role of clinical pharmacy service in HF drug therapy optimisation via improving beta-blocker prescription rates by from 24% to 38% and reducing digoxin rates from 34% to 23%. However, the service did not improve the overall guideline adherence levels or the prevalence of inappropriate prescribing. The survey explored some new aspects in HF practice, such as the urgent need for locally-drafted guidelines and the more significant implementation of clinical pharmacy service to optimise the implementation of guideline-led prescribing in routine clinical practice. Conclusion: This thesis has made a significant contribution to the knowledge and generated a much needed conceptual understanding of the complexity of HF guideline-led prescribing. This work reflects the moderate adherence levels to guidelines and high prevalence of potentially inappropriate prescribing in the two countries. None of the prescribers either in Ireland or Egypt prescribed at least a renin-angiotensin system inhibitor to all HF patients despite the strong, long-standing evidence.
Gut microbiome-xenobiotic interactions: focus on drug metabolism
(University College Cork, 2020-03-06) Walsh, Jacinta; Griffin, Brendan T.; Hyland, Niall P.; Clarke, Gerard; Science Foundation Ireland
The fate and activity of drugs are frequently dictated not only by the host per se but also by the microorganisms present in the gastrointestinal tract. While the ever-increasing scientific breakthroughs have highlighted the influence of the gut microbiome on health and well-being, mechanistic insights on the role of the microbiota on the metabolism of orally administered therapeutics and endogenous signalling molecules remain relatively understudied. However, a growing body of evidence now suggests the gut microbiome can itself influence the actions of a range of drugs. This functional metabolic repertoire includes the capacity for drug activation, reactivation and detoxification by bacterial-derived enzymes, the consequences of which can be either beneficial or potentially harmful on the host. More recently, the ability of the microbiome to indirectly influence host metabolism has been suggested, but there remains only a rudimentary understanding of the molecular underpinnings and potential implications of this effect. Moreover, no study has extensively investigated the impact of the gut microbiome on drug efflux transporters. The overarching goal of this thesis was to further investigate gut microbiome-drug interactions by addressing some key outstanding questions in how it, both directly and indirectly, metabolises drugs and more specifically, what impact perturbations to its function or composition has on drug pharmacokinetics. To achieve this goal, in Chapter 2, an ex vivo metabolism assay, fecalase, was characterised to identify drugs susceptible to direct metabolism by bacterial-derived enzymes. Given variability in drug-metabolising enzymes can be a crucial source of inter-individual variability in drug response, we examined whether host related factors, including sex, age and genetics, can influence the drug-metabolising capacity of the gut microbiota while in Chapter 3, the primary objective was to explore the influence of perturbations of the gut microbiome on the drug-metabolising and transport capacity of the host. Fuelled by our findings illuminating the effects of microbiota-targeted interventions on metabolism by both the gut microbiota and host, we took a more integrated in vivo approach in Chapter 4 to enhance the understanding of how such manipulations may affect the pharmacokinetics of neuroactive drugs. Cumulatively, the results reveal that perturbations to the gut microbiome can introduce variability in both faecal enzymatic activity and the expression of host genes implicated in drug metabolism and transport. Moreover, the pharmacokinetic results draw attention to the capacity of the gut microbiome to alter the systemic concentrations of specific drugs. Finally, limitations of the fecalase model for assessment of bacterial-mediated drug metabolism using current approaches have been identified, and suggestions for future optimisation have been made. Successful exploitation of these prominent but neglected features of the gut microbiome has the potential to inform personalised medicine, and targeted nutritional approaches. To this end, this work has provided the impetus to identify mechanisms driving reciprocal drug-gut microbiota interactions, to guide the development of microbiome-targeted dietary or pharmacological interventions, with the potential to enhance drug efficacy or reduce drug side-effects.
The gut microbiota as a contributing factor to antipsychotic-induced weight gain and metabolic dysfunction
(University College Cork, 2013) Davey, Kieran; O'Mahony, Siobhain M.; Dinan, Timothy G.; Cryan, John F.
Schizophrenia represents one of the world’s most devastating illnesses due to its often lifelong course and debilitating nature. The treatment of schizophrenia has vastly improved over recent decades with the discovery of several antipsychotic compounds; however these drugs are not without adverse effects that must be addressed to maximize their therapeutic value. Newer, atypical, antipsychotics are associated with a compilation of serious metabolic side effects including weight gain, insulin resistance, fat deposition, glucose dysregulation and ensuing co-morbidities such as type II diabetes mellitus. The mechanisms underlying these side effects remain to be fully elucidated and adequate interventions are lacking. Further understanding of the factors that contribute these side effects is therefore required in order to develop effective adjunctive therapies and to potentially design antipsychotic drugs in the future with reduced impact on the metabolic health of patients. We investigated if the gut microbiota represented a novel mechanism contributing to the metabolic dysfunction associated with atypical antipsychotics. The gut microbiota comprises the bacteria that exist symbiotically within the gastrointestinal tract, and has been shown in recent years to be involved in several aspects of energy balance and metabolism. We have demonstrated that administration of certain antipsychotics in the rat results in an altered microbiota profile and, moreover, that the microbiota is required for the full scale of metabolic dysfunction to occur. We have further shown that specific antibiotics can attenuate certain aspects of olanzapine and risperidone–induced metabolic dysfunction, in particular fat deposition and adipose tissue inflammation. Mechanisms underlying this novel link appear to involve energy utilization via expression of lipogenic genes as well as reduced inflammatory tone. Taken together, these data indicate that the gut microbiota is an important factor involved in the myriad of metabolic complications associated with antipsychotic therapy. Furthermore, these data support the future investigation of microbial-based therapeutics for not only antipsychotic-induced weight gain but also for tackling the global obesity epidemic.
Gut microbiota-mediated bile acid metabolism: implications for oral drug absorption
(University College Cork, 2019) Enright, Elaine F.; Gahan, Cormac G.; Joyce, Susan; Irish Research Council; Fulbright Association
In recent years, it has been elucidated that, in addition to host genetics, the gut microbiome must be considered as a source of pharmacokinetic variability. As newly emerging drug candidates trend toward low solubility and/or permeability, biopharmaceutical properties that prolong gastrointestinal residence time, and thereby microbial contact, identifying and manipulating the microbial processes influencing drug disposition will have fruitful consequences for personalized healthcare. To date, pharmacokinetic research at the host-microbe interface has been primarily focussed on effects on drug metabolism, with minimal consideration to the absorption process (as reviewed in Chapter I). Thus, this thesis investigates a potential mechanism, ‘microbial bile acid metabolism’, by which the intricate interplay between the host and gut bacteria may affect the pre-absorption behaviour and uptake of orally administered drugs. Bile salts have long been appreciated within the pharmaceutical field to be efficient solubilizers of lipophilic drugs. It is also now known that bile salts are important signalling molecules, with the potential to regulate xenobiotic-processing genes via bile acid-activated receptors (BARs). As the size and composition of the bile acid pool is regulated by gut bacterial bile acid metabolism, we propose that inter-individual differences in drug response may be partly attributed to variations in this specific microbial function. In the intestine, host synthesized tauro- or glyco-conjugated bile acids are sequentially deconjugated and 7α-dehydroxylated by microbial enzymes. These biotransformative reactions augment the diversity and alter the physicochemical properties of the bile acid pool. Herein, the effect of bile acid deconjugation and dehydroxylation on bile salt micelle solubilization capacity (Chapter II and III), supersaturated formulation stability (Chapter IV), drug-processing gene expression (Chapter V and VI), as well as passive and active transport mechanisms (Chapter III and V) was investigated. Bile acid conjugation and, in particular, hydroxylation state were determined to significantly influence the phase behaviour of poorly water-soluble drugs (PWSDs). Firstly, dihydroxy bile salt micelles were shown to possess a greater solubilization capacity for PWSDs than trihydroxy counterparts. Dihydroxy bile acids were also observed to be more efficient crystallization inhibitors, and thereby significantly improved the stability of supersaturated solutions of atazanavir, a weakly basic PWSD, relative to trihydroxy species. In addition, the crystallization onset of atazanavir in media designed to mimic a range of representative healthy subject intestinal fluids exhibited a bile salt concentration-dependence, further indicating that gut microbial activity may influence crystallization kinetics in vivo by regulating bile acid pool size. Collectively, these findings suggest that: (1) microbial bile acid metabolism may impact intraluminal drug behaviour, and (2) that close attention should be paid to the concentration and composition of bile salts used in simulated intestinal media when assessing both crystalline and supersaturating formulations to improve in vitro-in vivo predictiveness. This thesis has also illustrated that bile salt conjugation and hydroxylation state can influence the transcription of genes encoding proteins involved in drug disposition. Furthermore, this work identified a novel mechanism by which unconjugated dihydroxy bile acids can affect drug uptake through inhibition of P-glycoprotein ATPase activity. Overall, our research sheds new light on the multitude of mechanisms by which microbial bile acid metabolism may influence the drug absorption process. This effect might be most significant in disease states where gut microbiota alterations are exaggerated.

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