Assoc Prof Jenny Schneider

Drug repurposing has potential to improve outcomes for high-grade serous ovarian cancer (HGSOC). Repurposing drugs with PARP family binding activity may produce cytotoxic effects through the multiple mechanisms of PARP including DNA repair, cell-cycle regulation, and apoptosis. The aim of this study was to determine existing drugs that have PARP family binding activity and can be repurposed for treatment of HGSOC. In silico ligand-based virtual screening (BLAZE) was used to identify drugs with potential PARP-binding activity. The list was refined by dosing, known cytotoxicity, lipophilicity, teratogenicity, and side effects. The highest ranked drug, efavirenz, progressed to in vitro testing. Molecularly characterized HGSOC cell lines, 3D hydrogel-encapsulated models, and patient-derived organoid models were used to determine the IC50 for efavirenz, cell death, apoptosis, PARP1 enzyme expression, and activity in intact cancer cells following efavirenz treatment. The IC50 for efavirenz was 26.43¿45.85 µM for cells in two dimensions; 27.81 µM¿54.98 µM in three dimensions, and 14.52 µM¿42.27 µM in HGSOC patient-derived organoids. Efavirenz decreased cell viability via inhibition of PARP; increased CHK2 and phosphor-RB; increased cell-cycle arrest via decreased CDK2; increased ¿H2AX, DNA damage, and apoptosis. The results of this study suggest that efavirenz may be a viable treatment for HGSOC.

5-fluorouracil (5-FU) and its oral formulation, capecitabine, are widely used in treating a range of malignancies, either alone or in combination with other antineoplastic drugs. Body surface area-based dosing is used for these agents, despite this approach leading to substantial variability in drug exposure and often resulting in either toxicity or treatment failure. Tailoring therapeutic regimens for individual patients using therapeutic drug monitoring (TDM) has been shown to significantly reduce toxicity and improve cancer outcomes. However, for optimum TDM, sample timing is crucial, along with the need for a venepuncture blood sample to obtain the plasma currently used for 5-FU measurement. In addition to complex blood sample handling requirements, large sample volume and frequent sampling required for pharmacokinetic analysis is another barrier to successfully implementing TDM in a healthcare setting. Microsampling is an alternative collection method to venepuncture, which, combined with the now readily available liquid chromatography mass spectrometry (LC-MS/MS) technology, overcomes the plasma-associated issues. It also has the significant advantage of enabling at home and remote sampling, thus facilitating 5-FU TDM in clinical practice. A LC-MS/MS method for simultaneous measurement of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine and 5-FU using Mitra® microsampling devices for sample collection was developed. A Shimadzu 8060 LC-MS/MS equipped with electrospray ionisation source interface, operated in positive and negative ion modes, with reversed-phase chromatographic separation was employed for sample analysis. Samples were extracted from Mitra® devices using acetonitrile containing stable isotope-labelled internal standards, sonicated, evaporated under vacuum and resuspended in 0.1 % formic acid before injection into the LC-MS/MS. Chromatographic separation was on a Luna Omega Polar C18 (100 × 2.1 mm, 1.6 µm) column with gradient elution of 0.1 % formic acid in water and acetonitrile. Total run time was 5 min, with the injection volume of 1 µL. The intra and inter-day imprecision ranged from 3.0 to 8.1 and 6.3¿13.3 % respectively. Accuracy ranged from 95 -114 % for all analytes. Lower limit of quantification with imprecision of < 19 % and accuracy between 89 and 114 % was 0.05 mg/L for 5-FU and 10 µg/L for other analytes. Assays were linear from 0.05 to 50 mg/L for 5-FU and 10¿10,000 µg/L for all other analytes. Analytes were stable on Mitra® devices for up to 9 months at room temperature, 2 years at -30 ¿ and 3 days at 50 ¿. The method was successfully applied for the analysis of samples from patients undergoing cancer treatment with 5-FU and capecitabine. Microsampling using volumetric absorptive microsampling proved to be as reliable as conventional blood collection for 5-FU and capecitabine. This sampling technique may lead to less invasive and better-timed sample collection for TDM, supporting dose optimization strategy.

Background and Objectives: The US Preventative Services Taskforce recommends screening adults for depression in primary care where adequate systems are established to ensure accurate diagnosis, effective treatment and follow-up. However, there is currently no consensus on which screening tool is most suitable for use in primary healthcare. We aim to systematically review the literature for operating characteristics of depression screening tools capable of self-administration in primary healthcare and meta-analyse the psychometric characteristics of these tools to determine their performance and accuracy. Methods: An electronic literature search of EMBASE, Medline and CINAHL Complete was conducted from January 1982 to September 15, 2019 using the keywords: depression, screening, primary healthcare and adult. General and psychometric characteristics were extracted for screening tools studied in primary healthcare only when assessed against a 'reference-standard'. Results: Eighty-one studies from 22 countries were included in the review. Forty unique depression screening tools suitable for self-administration were identified in studies yielding 138 psychometric data sets. Based on ease of administration, 18 screening tools were suitable for use in primary healthcare. Of the tools meta-analysed, only the PHQ-9 and WHO-5 displayed superior accuracy and were easily administered. Conclusion: Although numerous depression screening tools are suitable for use in primary care based on ease of administration, the PHQ-9 was the most widely assessed tool and displayed superior DOR, a-ROC, specificity and LR +. Our review supports the use of the PHQ-9 as a brief, easily administered depression screening tool with superior discriminatory performance and robust psychometric characteristics in primary care settings.

Background: The most important two medicinal cannabinoids are ¿9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Vaporised administration is superior due to its higher systemic availability, lower individual variability and faster drug delivery. Although it is common THC is co-administered with CBD, the influence of CBD on the pharmacokinetics, especially the systemic availability of THC after vaporised administration, is unknown. Aims: To investigate the influence of different doses of co-administered CBD on the systemic availability of THC, and to compare the availability of THC and CBD in a sample of frequent and infrequent cannabis users. Methods: The study used a randomised, double-blind, crossover placebo-controlled design. THC and/or CBD in ethanol was vaporised and inhaled. Plasma concentrations of THC and CBD were analysed. The THC data created in this study were pooled together with published THC pharmacokinetic data in order to cover all the phases of THC disposition. Population pharmacokinetic model of THC was developed based on the pooled data. The model of CBD was developed based on the data created in this study. Results: Population pharmacokinetic models of THC and CBD were developed. With concomitant inhalation of high-dose CBD, the systemic availability of THC decreased significantly. Frequent cannabis users appeared to have higher systemic availability of THC and CBD when high-dose CBD was administered. Conclusions: The results observed in this study are useful for guiding future pharmacokinetic studies of medicinal cannabinoids, and for development of dosing guidelines for medical use of cannabis in the 'real-world' setting.

Background and purpose: Effective, safe, and patient-centred dispensing is a core task of community pharmacists. Entrustable professional activities (EPAs) offer a way of defining and assessing these daily practice activities. Although EPAs have become popular within competency-based medical education programs, their use is new to pharmacy education and assessment. Educational activity and setting: A simulation-based assessment framework containing a scale of entrustment was developed to evaluate the readiness of Year 4 undergraduate pharmacy students to safely manage the supply of prescribed medicine(s) in a community pharmacy. The assessment framework was piloted in a fourth year "Transition to Practice" course with 28 simulation-based assessments conducted. Findings: An entrustment framework was developed and implemented successfully with Year 4 undergraduate pharmacy students. The EPA for medicine dispensing integrates competency domains that include information gathering, providing patient-centred care, clinical reasoning, medicine dispensing, and professional communications. On a scale ranging from level 1 to level 5, the majority (73%) of entrustment ratings were level 2 or level 3; and of the students who achieved different ratings between clinical scenarios, 75% of students improved on their second simulation attempt. There was a strong correlation between the global EPA ratings with the total score achieved across the domains. Using simulation-based assessment, entrustment decision making can be incorporated in "entry to profession" undergraduate and postgraduate pharmacy courses to assess students' readiness to transition between learning and professional practice.

Remifentanil is a short acting opioid currently used in anesthesia and as an analgesic. This paper describes a simple, fast HPLC-MS/MS methodology that allows detection of remifentanil in low volume plasma samples. Acetonitrile protein precipitation is used for sample extraction and clean up. The assay has a lower limit of detection of 0.25 ng/mL and a 3 min run time.

Endocannabinoid pharmacology is now relatively well understood with a number of endocannabinoids and endogenous cannabinoid neurotransmitters identified and the pharmacokinetics relatively well ascertained. Further, the cannabinoid receptors are now molecularly and pharmacologically characterised and the cell processes involved in endocannabinoid transcription, synthesis, post-translational modification and protein expression are reported. Endogenous cannabinoids have been shown to have key roles in immune and pain pathways and neuro-behavioural signalling including appetite regulation. Significant recent interest has thus been shown in understanding these pathways to guide the development of agents that inhibit the natural catabolism of endogenous cannabinoids to modify pain and appetite, and to synthesise antagonists for the treatment of disease such as obesity. This research is concurrent with the renewed clinical interest in exogenous cannabinoids and their use in disease. However, the complex pharmacology and physiological effects of exogenous cannabinoids, either as individual components or in combination, as extracts or via administration of the whole plant in humans, are less well known. Yet as with all other therapeutics, including those derived from plants, knowledge of the pharmacokinetics and dynamics of the complete plant, the individual chemical molecules and their synthetic versions, including formulations and excipients is a standard part of drug development. This article covers the key pharmacological knowledge required to guide further exploration of the toxicity and efficacy of different cannabinoids and their formulations in blinded placebo-controlled studies.

This study analyzed clinically actionable pharmacogenotypes for clopidogrel, warfarin, statins, thiopurines, and tacrolimus using microarray data for 2121 participants (55¿85 years) from the Australian Hunter Community Study (HCS). At least 74% of participants (95% confidence interval [CI]: 72%¿76%) had strong level evidence for at least one medium- or high-risk actionable genotype that would trigger a change in standard therapy under current international recommendations. About 14% of these participants (95% CI: 12%¿16%) were taking medication potentially affected by the genotype in question. Furthermore, ~2.6% of all participants with medication data (95% CI: 1.4%¿3.8%) had a high-risk clinically actionable genotype for a medication to which they were exposed. This represents a considerable number of people at the population level. Although relationships between genotype and health outcomes remain contentious, pharmacogenotyping of multiple variants simultaneously may have considerable potential to improve medication safety and efficacy for older people in the community.

Objective: To evaluate the feasibility of providing diabetes risk assessment at community pharmacy level in Australia and Thailand from organizational aspects. Methods: The intervention study was conducted in eight community pharmacies in New South Wales, Australia, and six community pharmacies in Central Thailand. Diabetes risk assessment tools were applied to determine the risk of developing type 2 diabetes. An open-ended question was asked to solicit the willingness-to-pay value for the service. A semistructured interview was conducted with participating pharmacists to solicit the perceived facilitators and barriers in providing the service. Results: There were a total of 132 and 185 participants, with the ratio of participants in the three risk categories of low, intermediate, and high being 1:4:11 and 2:1:1.5 for Australia and Thailand, respectively. More Thai participants were willing to pay for the service (72.4% vs. 18.9%; P = 0.0001). Pharmacists from both countries agreed that providing risk assessment would increase health awareness and assist in dampening the burden of disease. A major barrier is time and staff shortage. Support from the government and collaboration among health care providers were major facilitators from Thai pharmacists' perspective, whereas remuneration was a major facilitator from Australian pharmacists' perspective. Conclusions: Pharmacists in both countries agreed that this intervention would contribute to produce positive health benefits. Differences in advantages and barriers as well as in the proportion of consumers willing to pay for the service demonstrated that it is essential for pharmacists (particularly in developing countries) to be aware of the pitfalls of copying practice initiatives in developed countries without any consideration of the local health care environment.

Background: Intramuscular droperidol is used increasingly for sedation of aggressive and violent patients. This study aimed to characterise the pharmacokinetics of intramuscular droperidol in these patients to determine how rapidly it is absorbed and the expected duration of measurable drug concentrations. Methods: We undertook a population pharmacokinetic analysis of a subgroup of patients from a clinical trial comparing droperidol and midazolam: 17 receiving 5¿mg and 24 receiving 10¿mg droperidol. Droperidol was measured using high-performance liquid chromatography. Pharmacokinetic modelling was performed under a nonlinear mixed effects modelling framework (NONMEM v7.2). The model was used to simulate concentration time profiles of three typical doses, 5¿mg, 10¿mg and 10¿mg¿+¿10¿mg repeated at 15¿min. Results: A two-compartment first-order input with first-order output model fitted the data best. The absorption rate constant was poorly characterised by the data and an estimate of the first order rate constant of absorption when fixed to 10¿h¿1provided a stable model and lowest objective function. This represents extremely rapid absorption with a half-life of 5¿min. The final model had a clearance of 41.9¿l¿h¿1and volume of distribution of the central compartment of, 73.6¿l. Median and interquartile range of initial (alpha) half-life was 0.32¿h (0.26¿0.37¿h) and second (beta) half-life was 3.0¿h (2.5¿3.6¿h). Simulations indicate that 10¿mg alone provides an 80% probability of being above the lower limit of quantification (5¿µg¿l¿1) for 7¿h, 2¿h longer than for 5¿mg. Giving two 10¿mg doses increased this duration to 10¿h. Conclusions: Intramuscular droperidol is rapidly absorbed with high therapeutic concentrations after 5 and 10¿mg doses, and supports clinical data in which droperidol sedates rapidly for up to 6¿h.

Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.