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BACKGROUND In 2018, an innovative, State government funded cannabis medicines drug information service was established for health professionals in New South Wales (NSW). The NSW Cannabis Medicines Advisory Service (CMAS) provides expert clinical guidance and support to medical practitioners considering prescribing a cannabis medicine to their patient(s). AIMS This research examines quality assurance and patient outcomes related to enquirers' experience with NSW CMAS. METHODS Data collection involved an online, anonymous survey with two components. Following a health professional enquiry, quality assurance data was collected about the enquirers' experience with NSW CMAS. The second survey focused on patient outcomes and provides real-world observational data about cannabis medicines safety and effectiveness across a wide range of indications. RESULTS Data collection occurred between January 2020 and June 2021. Preliminary analyses were based on 68 quality assurance and 50 patient outcomes survey responses. General practitioners represented the highest proportion of survey responses (n = 33, 49%). The most common enquiry involved 'patient-specific advice' (n = 50, 74%). Patient-specific information provided by the service was mainly used for prescribing decision support (n = 45, 90%). CONCLUSIONS Preliminary findings highlight the impact of an innovative cannabis medicines drug information service in supporting health professional clinical practice in an area of rapid knowledge translation. Quality assurance data indicates that the service is perceived well by the majority of enquirers. Patient outcomes data across a wide range of indications suggest some effectiveness and a reasonable safety profile for prescribed cannabis medicines for most patients. This article is protected by copyright. All rights reserved.

Although therapeutic drug monitoring (TDM) is an important tool in guiding drug dosing for other areas of medicine including infectious diseases, cardiology, psychiatry and transplant medicine, it has not gained wide acceptance in oncology. For imatinib and other tyrosine kinase inhibitors, a flat dosing approach is utilised for management of oral chemotherapy. There are many published studies examining the correlation of blood concentrations with clinical effects of imatinib. The International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) determined that there was a need to examine the published literature regarding utility of TDM in imatinib therapy and to develop consensus guidelines for TDM based on the available data. This article summarises the scientific evidence regarding TDM of imatinib, as well as the consensus guidelines developed by the IATDMCT.

Body surface area (BSA)–based dosing of irinotecan (IR) does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variabilities. Functional hepatic nuclear imaging (HNI) and excretory/metabolic/PD pharmacogenomics have shown correlations with IR disposition and toxicity/efficacy. This study reports the development of a nonlinear mixed-effect population model to identify pharmacogenomic and HNI-related covariates that impact on IR disposition to support dosage optimization. Patients had advanced colorectal cancer treated with IR combination therapy. Baseline blood was analysed by Affymetrix DMET™ Plus Array and, for PD, single nucleotide polymorphisms (SNPs) by Sanger sequencing. For HNI, patients underwent 99mTc-IDA hepatic imaging, and data was analysed for hepatic extraction/excretion parameters. Blood was taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1. Population modelling utilised NONMEM version 7.2.0, with structural PK models developed for each moiety. Covariates include patient demographics, HNI parameters and pharmacogenomic variants. Analysis included (i) PK data: 32 patients; (ii) pharmacogenomic data: 31 patients: 750 DMET and 22 PD variants; and (iii) HNI data: 32 patients. On initial analysis, overall five SNPs were identified as significant covariates for CLSN38. Only UGT1A3_c.31 T > C and ABCB1_c.3435C > T were included in the final model, whereby CLSN38 reduced from 76.8 to 55.1%. The identified UGT1A3_c.31 T > C and ABCB1_c.3435C > T variants, from wild type to homozygous, were included in the final model for SN38 clearance.

Although cannabis has been used for several thousand years, the exact composition of the cannabinoids patients are administered for different symptoms has remained largely unknown. While this absence of catalogued information may be accepted in some cultures, the use of cannabis as a human product in the registered medicines setting requires knowing its composition so that doses can be standardised between patients. This is particularly so in clinical trials that are currently under way to determine the efficacy of a product. Although the major cannabinoids of interest to prescribers are well known – tetrahydrocannabinol and cannabidiol and the corresponding acids tetrahydrocannabinolic acid and cannabidiolic acid, the cannabis plant contains many more phytocannabinoids. We have developed and validated a robust and fast (11 min) isocratic HPLC method for the analysis of 17 phytocannabinoids. The method had an analytical range of 1–150 μg mL−1 for tetrahydrocannabinolic acid and cannabidiolic acid, 0.5–75 μg mL−1 for tetrahydrocannabinol and cannabidiol, and 0.5–20 μg mL−1 for the remaining 13 cannabinoids. The method had excellent repeatability with a relative standard deviation of between 5 and 14 % and a bias of between –8.6 and 6 % for the 17 cannabinoids. The method was applied to the analysis of medicinal cannabis products, including both flos and oils with results matching the supplier’s certificate of analysis. This simple fast isocratic method with basic HPLC equipment can be easily transferred to any analytical laboratory interested in the identification and quantitation of cannabinoids.

With cannabis medicines now obtaining legal status in many international jurisdictions (generally on the authorisation of a medical professional), a rapid increase in consumer demand for access to cannabis as a therapeutic option in the treatment and management of a range of indications is being noted. Despite this accessibility, knowledge on optimal use is lacking. Further drug development and clinical trials at regulatory standards are necessary both if a better understanding of the efficacy of cannabis medicines, optimal product formulation and indication-specific dosing is needed and to ensure the broader quality and safety of cannabis medicines in the clinical setting.To enable this, clinical, academic and public calls for the undertaking of rigorous clinical trials to establish an evidence base for the therapeutic use of cannabis medicines have been made internationally. While this commitment to undertake human studies with cannabis medicines is welcomed, it has highlighted unique challenges, notably in the review stages of ethics and governance. This often results in lengthy delays to approval by Human Research Ethics Committees (herein ‘HREC’, Australia’s nomenclature for Institutional Review Boards) and trial commencement. A principal concern in these cases is that in contrast to clinical trials using other more conventional pharmaceutical products, trials of cannabis medicines in humans often involve the use of an investigational product prior to some (or any) of the preclinical and pharmaceutical safety issues being established. This paucity of data around product safety, potential drug interactions, continuity of supply, shelf life and product storage results in apprehension by HRECs and governance bodies to endorse trials using cannabis medicines.This manuscript draws from the experiences of Australian researchers and staff involved in clinical trials of cannabis medicines to describe some of the common difficulties that may be faced in the HREC approval process. It also presents practical advice aimed to assist researchers, HRECs and governance officers navigate this complex terrain. While the authors’ experiences are situated within the Australian setting, many of the barriers described are applicable within the international context and thus, the solutions that have been proposed are typically adaptive for use within other jurisdictions.

Objective: The research evaluated point-of-care resources for scope, completeness, and consistency of information describing interactions between therapeutic drugs and drugs of abuse (DoA).Methods: A cross-sectional evaluation study was conducted focusing on seven resources: Clinical Pharmacology, Facts & Comparisons eAnswers, Lexicomp Online, Micromedex, Drug Interactions Analysis and Management, Drug Interaction Facts, and Stockley’s Drug Interactions. A sample of clinically relevant interactions was developed through review of tertiary literature and resources, and input was solicited from subject matter experts. Entries from each resource for each interaction were evaluated for scope (i.e., whether there was an entry for the interaction); completeness (i.e., whether there was information addressing mechanism; clinical effects, severity, course of action, and level of certainty, described as a median rating on a 5-point scale); and consistency (i.e., whether the information in the resource was similar to the majority) among resources with an entry.Results: Following review by subject matter experts, the final sample contained 159 interactions. Scope scores ranged from 0.6% (Drug Interactions Analysis and Management) to 43.4% (Lexicomp Online). Completeness scores ranged from 2 (interquartile range [IQR] 0 to 3, Stockley’s Drug Interactions) to 5 (IQR 5 to 5, Drug Interaction Facts, Micromedex, Facts & Comparisons eAnswers). Consistency scores ranged from 30.8% (Stockley’s Drug Interactions) to 87.1% (Clinical Pharmacology) for severity and from 15.4% (Facts & Comparisons eAnswers) to 71.4% (Drug Interaction Facts) for course of action.Conclusions: Although coverage of drug-DoA interactions was low and content was often inconsistent among resources, the provided information was generally complete.

People with chronic disease often have poor comprehension of their disease and medications, which can negatively affect health outcomes. In a randomised‐controlled trial, we found that patients with decompensated cirrhosis who received a pharmacist‐led, patient‐oriented education and medication management intervention (n = 57) had greater knowledge of cirrhosis and key self‐care tasks compared with usual care (n = 59). Intervention patients also experienced improved quality of life. Dedicated resources are needed to support implementation of evidence‐based measures at local centres to improve outcomes.

Objective: To describe telehealth interventions and determine their effect on medication adherence for patients with type 2 diabetes, hypertension, and/or dyslipidemia. Data Sources: PubMed/MEDLINE, EMBASE, Cochrane, CINAHL Plus, PsycINFO, Academic Search Ultimate, International Pharmaceutical Abstracts, Scopus, Web of Science, WHO Global Index Medicus, association websites, and gray literature were searched from January 1, 1998, to December 31, 2019. Study Selection and Data Extraction: Eligible studies reported eHealth, mobile health, and telehealth interventions for adult patients prescribed medications for chronic condition management (eg, type 2 diabetes, hypertension, and/or dyslipidemia). Studies were required to evaluate medication adherence outcomes (eg, medication possession ratio [MPR], proportion of days covered (PDC)]. Randomized controlled trials, cohort studies, and controlled before-and-after studies were included. Multiple reviewers independently extracted data and evaluated risk of bias. Data Synthesis: Of 8693 studies identified, 13 reported either an MPR or PDC and were included in the systematic review. The systematic review demonstrated that electronic health (eHealth) and telehealth interventions were successful at improving medication adherence, whereas mobile health interventions did not improve medication adherence. Relevance to Patient Care and Clinical Practice: This systematic review highlighted the available research and findings of studies assessing interventions to improve medication nonadherence among patients with type 2 diabetes, hypertension, and/or dyslipidemia. The evaluated findings lend support to the need for targeted medication adherence interventions based on patient population and practice settings. Conclusions: Telehealth modalities include telephonic outreach and specialized tools designed to increase health literacy. eHealth and telehealth medication adherence interventions were associated with improved MPR and/or PDC rates.

Background The most important two medicinal cannabinoids are Δ9 -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: The presence of elevated systemic inflammation in people with advanced non-small cell lung cancer (NSCLC) is associated with significantly shorter survival following carboplatin-based chemotherapy. Objective: This study investigated whether novel factors, such as systemic inflammation [platelet–lymphocyte ratio (PLR) and neutrophil–lymphocyte ratio (NLR)], impact carboplatin pharmacokinetics and drug utilisation. The study also examined the ability of current and alternate dosing regimens to meet therapeutic targets. Methods: Seventy-two people with advanced NSCLC treated with carboplatin-based (460–1050 mg) doublet chemotherapy were recruited and pharmacokinetic data (n = 61) were analysed using non-linear mixed modelling. Covariate analysis was performed to investigate the impact of standard and novel patient characteristics of carboplatin pharmacokinetics. A Monte Carlo simulation of 100,000 representative NSCLC patients evaluated the ability of the Calvert formula and novel dosing strategies to achieve the targeted therapeutic range. The associations between systemic inflammation and chemotherapy drug utilisation (cycles received, relative dose intensity (RDI) and second-line uptake) and clinical endpoints were also investigated in the pharmacokinetic cohort, and two independent cohorts of people with advanced NSCLC from the Chemotherapy Dosing in Cancer-Related Inflammation (CDCRI) database that were administered carboplatin–paclitaxel (n = 37) or carboplatin–gemcitabine (n = 358). Results: In all cohorts, 25–53% of people had elevated systemic inflammation (NLR > 5 or PLR > 300). In the pharmacokinetic cohort, no patients achieved the desired therapeutic target of carboplatin. Carboplatin exposure was related to renal function, as estimated using the Cockcroft–Gault formula, albumin and inflammation (NLR). In the pharmacokinetic cohort, increasing carboplatin area under the curve (AUC) correlated with greater reductions in red blood cells and haemoglobin. In this cohort, the average measured AUC of partial responders was 2.4 mg·min/mL. Also in the pharmacokinetic cohort, only 12% of people with an NLR > 5 received four or more cycles of chemotherapy, compared with 62% of patients with an NLR ≤ 5 (p 5 also received less cycles (four or more cycles, 41% vs. 60%; p 5 had 12 months less median survival compared with people with an NLR ≤ 5 (6.5 vs. 18 months; p = 0.08). Similarly, overall survival was significantly shortened in people in the CDCRI cohort receiving carboplatin–gemcitabine with an NLR > 5 compared with those with an NLR ≤ 5 (7 vs. 12 months; p

© 2019 The Author(s). Background: Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids, but there is little high quality evidence to guide clinicians. This study aims to define the role of cannabidiol (CBD) in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. Methods and design: This study is a multicentre, randomised, placebo controlled, two arm, parallel trial of escalating doses of oral CBD. It will compare efficacy and safety outcomes of a titrated dose of CBD (100 mg/mL formulation, dose range 50 mg to 600 mg per day) against placebo. There is a 2-week patient determined titration phase, using escalating doses of CBD or placebo to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. Discussion: A major strength of this study is that it will target symptom burden as a whole, rather than just individual symptoms, in an attempt to describe the general improvement in wellbeing previously reported by some patients in open label, non controlled trials of medicinal cannabis. Randomisation with placebo is essential because of the well-documented over reporting of benefit in uncontrolled trials and high placebo response rates in cancer pain trials. This will be the first placebo controlled clinical trial to evaluate rigorously the efficacy, safety and acceptability of CBD for symptom relief in advanced cancer patients. This study will provide the medical community with evidence to present to patients wishing to access medicinal cannabis for their cancer related symptoms. Trial registration number: ALCTRN12618001220257 Registered 20/07/2018.

Objective: Research was conducted on the embedded librarian program at The University of Arizona College of Pharmacy and the Health Sciences Library to understand how this service is relevant to users and identify the potential for further improvement. This study examined users’ information-seeking behaviors and considered the implications for the effectiveness of the embedded librarian service. Methods : The authors conducted 18 semi-structured interviews of faculty, researchers, and students at the College of Pharmacy to obtain descriptive accounts of how they seek information, manage information, and use the library and library services. The authors examined the interview transcripts through qualitative descriptive analysis. Res ults : The interview responses confirm that users seek information outside of the physical library and tend to ask their peers for information or assistance in obtaining information. They mostly feel comfortable in searching, but some of them may lack sufficient search skills and tend to use a few known databases. While those who are familiar with the librarian seek the librarian’s assistance more often, others tend not to seek the librarian’s assistance. The ways they manage information vary, which requires customized assistance. Conclusions: The close proximity of a physically embedded librarian is beneficial to users and positions the librarian to provide proactive assistance in the existing user information-seeking behavior environment. While some users do not seek assistance, the embedded librarian can provide proactive assistance in such areas as making users aware of other database options and helping them choose relevant databases and effectively manage information.

Aim This Phase I open label study examined pharmacokinetics, safety, and tolerability of escalating doses of a combination cannabinoid medication (1:1 ratio THC:CBD) in patients with chronic non-cancer pain (CNCP) on high dose opioid analgesia. Methods Nine people with CNCP and oral morphine equivalent daily dose of ≥60mg were recruited. Blood concentrations of THC, 11-hydroxytetrahydrocannabinol (OH-THC), 11-nor-9-carboxy-tetrahydrocannabinol (COOH-THC) and CBD were assayed weekly. Concentrations were measured after a single dose of 2.5mg THC/2.5mg CBD up to 12.5mg THC/12.5mg CBD on Day 29. Follow-up was on Day 36 after 7 day washout. Secondary outcome data encompassed pain, mood, and sleep parameters. Results The parent THC, CBD, OH-THC, COOH-THC were detected at most time points. In general, the concentration of all analytes increased until 2 hours post-administration, decreasing to approximately pre-dose concentrations by 8 hrs. There was considerable inter- and intra-individual variability. The study medication was well tolerated. Eight participants reported at least one Adverse Event (AE), with a total of 62 AEs; most common were euphoric mood, headache, and agitation, none classified as severe. There was no significant change to pain severity self-ratings, nor use of pain medications. Improvements in pain interference scores, mood, and some sleep parameters were observed. Conclusion The THC:CBD formulation was tolerated well in a CNCP patient group. Between-participant variability supports personalized dosing and “start low-go slow” titration. Improvements in pain, mood, and sleep parameters suggest that on relatively low dosages clinical effects are apparent. To validate and quantify findings a comparison placebo group study is needed.

AIM Vancomycin guidelines for therapeutic drug monitoring (TDM) aim to maximise efficacy while minimising toxicity and resistance. Vancomycin is effective against Staphylococcus aureus when it achieves area under the concentration-time curve (AUC)/minimum inhibitory concentration (MIC) > 400. Studies in children have shown that target trough concentrations poorly correlate to AUC/MIC > 400; however, they are used in practice for clinical convenience. This review in paediatric inpatients aims to audit performance against TDM guidelines and consider what changes are needed to optimise vancomycin monitoring. METHODS Vancomycin prescriptions in patients younger than 18 years old were collected over a 15-month period. Primary outcome measures were vancomycin initial dose (mg/kg/day) and the timing and result of first trough concentration (mg/L). Secondary outcome measures were the numbers achieving recommended targets and whether appropriate dose adjustments were made in response to TDM. RESULTS A total of 133 courses reached the time when TDM should occur. Average patient age was 6.5 years, and the average initial dose was 52.55 mg/kg/day (range 19.05-86.54 mg/kg). Only 25% of courses (n = 34) had a trough concentration measured at the recommended time. The mean trough concentration was 11.6 mg/L (range

Two PD-1 (pembrolizumab, nivolumab) and one PD-L1(atezolizumab) inhibitors are approved for previously treated advanced non-small cell lung cancer but have not been compared in head-to-head trials.A network meta-analysis was conducted to compare efficacy/safety of PD-1/PD-L1 inhibitors.In five-trials (including long-term updates) with docetaxel as common comparator there were no differences in OS and PFS between PD-1/PD-L1 inhibitors. Pembrolizumab (odds ratio(OR) = 2.22, 95%CrI = 1.28-3.70) and nivolumab (OR = 1.92, 95%CrI = 1.15-3.23) had higher ORRs than atezolizumab and at PD-L1 expression ≥50% and ≥1%. Probabilistically, pembrolizumab ranked first in OS and ORR, and in OS sub-analyses for adenocarcinoma, EGFR-mutant, ECOG-score-1, male, and age65 years. Nivolumab ranked first in PFS, and in OS sub-analyses for squamous-cell disease, EGFR-wild-type, and ECOG-score-0. Pembrolizumab and nivolumab ranked the best option for most of adverse events.While pembrolizumab and nivolumab prevailed in rank in OS and ORR benefit, patient characteristics, safety and tolerance should be considered in treatment decision-making.

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 l...

Drug development for cancer chemotherapy has an interesting history. A mix of serendipity, animal, cell line, and standard pharmacological principles of dose, dose-response, dose-concentration, dose intensity and combination therapies have been used to develop optimal dosing schedules. However in practice, significant gaps in the translation of preclinical to clinical dosing schedules persist, and clinical development has instead moved to new drug development. A older chemotherapies are still the backbone of most solid tumour schedules, therapeutic drug monitoring has emerged as a method for optimising the dose for individual patients.

The role of general practitioners in cancer care has expanded in recent years. However, little is known about utilization of primary health care (PHC) services by patients with cancer, particularly among socio-economically disadvantaged groups. We describe utilization of PHC services by patients with cancer, and the nature of the care provided. The study focuses on a disadvantaged group in Australia, namely Indigenous Australians. A retrospective audit of clinical records in ten PHC services in Queensland, Australia. Demographic and clinical data of Indigenous Australians diagnosed with cancer during 2010–2016 were abstracted from patient’s medical records at the PHC services. The rates of cancer-related visits were calculated using person years at risk as a denominator. A total of 138 patients’ records were audited. During 12 months following the cancer diagnosis, patients visited the PHC service on average 5.95 times per year. Frequency of visits were relatively high in remote areas and among socioeconomic disadvantaged patients (IRR = 1.87, 95%CI 1.61–2.17; IRR = 1.79, 95%CI 1.45–2.21, respectively). Over 80% of visits were for seeking attention for symptoms, wound care, and emotional or social support. Patients who did not undergo surgery, had greater comorbidity, received chemotherapy and/or radiotherapy, and male gender had significantly greater rate of visits than their counterparts. The frequency of utilization of PHC services, especially by patients with comorbidities, and the range of reasons for attendance highlights the important role of PHC services in providing cancer care. The reliance on PHC services, particularly by patients in remote and disadvantaged communities, has important implications for appropriate resourcing and support for services in these locations.

Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p

Tacrolimus is one of the most widely used liver transplant medications. With the increasing number of obese patients requiring liver transplants, knowledge of the effect of body size affecting post-transplant outcomes e.g. drug exposure is increasingly required. 1) To investigate whether patient body size (i.e. total body weight) affect trough plasma concentrations of tacrolimus when a standard mg/kg dosing regimen is used; 2) To investigate whether obese patients have different number of plasma concentrations outside the therapeutic range compared to the non-obese patients in the first months after liver transplant. Using a transplant database, data tacrolimus concentrations were available for 69 patients. Tacrolimus was initially dosed at a standard 0.1mg/kg/day after liver transplant, and adjusted to maintain a target trough concentration. Trough blood samples, phenotypic and outcome variables were analysed. Trough concentrations were similar between the obese and non-obese patients (p>0.05) at each sampling day. At day-7 post-transplant, 85.7% and 79.5% of the observed plasma concentrations were outside the recommended therapeutic range for the obese and the non-obese patients respectively; at day-30, 52.9% and 57.4% and at 6 months, 18.7% and 27.5%. In the first week post-transplant, tacrolimus trough concentrations after standard mg/kg dosing post liver transplant appear to be corrected by total body weight. Obese patients have similar number of trough plasma concentrations outside the therapeutic range compared to the non-obese patients. This article is protected by copyright. All rights reserved.

Repurposing the large arsenal of existing non-cancer drugs is an attractive proposition to expand the clinical pipelines for cancer therapeutics. The earlier successes in repurposing resulted primarily from serendipitous findings but more recently, drug or target-centric systematic identification of repurposing opportunities continues to rise. Kinases are one of the most sought-after cancer drug targets over the last three decades. There are many non-cancer approved drugs that can inhibit kinases as “off-targets” as well as many existing kinase inhibitors that can target new additional kinases in cancer. Identifying cancer-associated kinase inhibitors through mining commercial drug databases or new kinase targets for existing inhibitors through comprehensive kinome profiling can offer more effective trial-ready options to rapidly advance drugs for clinical validation. In this review, we argue that drug repurposing is an important approach in modern drug development for cancer therapeutics. We have summarized the advantages of repurposing, the rationale behind this approach together with key barriers and opportunities in cancer drug development. We have also included examples of non-cancer drugs that inhibit kinases or are associated with kinase signalling as a basis for their anti-cancer action. Refereed/Peer-reviewed

Monoclonal antibodies (Mabs) have become key drugs in cancer treatment, either as targeted therapies or more recently as immune checkpoint inhibitors (ICIs). The fact that only some patients benefit from these drugs poses the usual question in the field of onco‐hematology: that of the benefit of individual dosing and the potential of therapeutic drug monitoring (TDM) to carry out this individualization. However, Mabs present unique pharmacological characteristics for TDM, and the pharmacokinetic–pharmacodynamic relationship observed should be interpreted differently than that observed for conventional drugs and small molecules. This pharmacology practice review has been summarized from a public debate between the authors at the International TDM and Clinical Toxicology meeting in Banff, 2020, regarding the potential roles of TDM in the Mab/ICI setting., This pharmacology practice review has been summarized from a public debate between the authors at the International therapeutic drug monitoring (TDM) and Clinical Toxicology meeting in Banff, 2020, regarding the potential roles of TDM in the Monoclonal Antibody/Checkpoint Inhibitors setting.

Refereed/Peer-reviewed

Aim: To explore health professionals’ perspectives on communication, continuity and between-service coordination for improving cancer care for Indigenous people in Queensland.Methods: Semi-structured interviews were conducted in a purposive sample of primary health care (PHC) services in Queensland with Indigenous and non-Indigenous health professionals who had experience caring for Indigenous cancer patients in the PHC and hospital setting. The World Health Organisation integrated people-centred health services framework was used to analyse the interview data.Results: Seventeen health staff from six Aboriginal Community Controlled Services and nine health professionals from one tertiary hospital participated in this study. PHC sites were in urban, regional and rural settings and the hospital was in a major city. Analysis of the data suggests that timely communication and information exchange, collaborative approaches, streamlined processes, flexible care delivery, and patient-centred care and support were crucial in improving the continuity and coordination of care between the PHC service and the treating hospital.Conclusion: Communication, collaboration and care coordination are integral in the provision of quality cancer care for Indigenous Australians. It is recommended that health policy and funding be designed to incorporate these aspects across services and settings as a strategy to improve cancer outcomes for Indigenous people in Queensland. Publisher's Note: A corrigendum relating to this article has been published at http://doi.org/10.5334/ijic.5641.

Background Despite improvements in medical care, patients with advanced cancer still experience substantial symptom distress. There is increasing interest in the use of medicinal cannabinoids but little high-quality evidence to guide clinicians. This study aims to define the role of a 1:1 delta-9-tetrahydrocannabinol/cannabidiol (THC/CBD) cannabinoid preparation in the management of symptom burden in patients with advanced cancer undergoing standard palliative care. Methods and design One hundred fifty participants will be recruited from five sites within the Queensland Palliative Care Research Group (QPCRG) and randomly assigned to an active treatment or placebo group. This study is a pragmatic multicentre, randomised, placebo-controlled, two-arm trial of escalating doses of an oral 1:1 THC/CBD cannabinoid preparation. It will compare efficacy and safety outcomes of a titrated dose (10 mg/10 mg/mL oral solution formulation, dose range 2.5 mg/2.5 mg–30 mg/30 mg/day) against placebo. There is a 2-week patient-determined titration phase, using escalating doses of 1:1 THC/CBD or placebo, to reach a dose that achieves symptom relief with tolerable side effects. This is then followed by a further 2-week assessment period on the stable dose determined in collaboration with clinicians. The primary objective is to assess the effect of escalating doses of a 1:1 THC/CBD cannabinoid preparation against placebo on change in total symptom score, with secondary objectives including establishing a patient-determined effective dose, the change in total physical and emotional sores, global impression of change, anxiety and depression, opioid use, quality of life and adverse effects. Discussion This will be the first placebo-controlled clinical trial to rigorously evaluate the efficacy, safety and acceptability of 1:1 THC/CBD for symptom relief in advanced cancer patients. This study will allow the medical community to have some evidence to present to patients wishing to access cannabis for their symptoms caused by advanced malignancy. Trial registration ACTRN, ACTRN12619000037101 . Registered on 14 January 2019. Trial Sponsor: Mater Misericordiae Limited (MML) and Mater Medical Research Institute Limited (MMRI)—Raymond Terrace, South Brisbane, Brisbane, QLD, Australia

In 2016 Fedson stated …. “For almost two decades, leading scientists and health officials have warned that we must prepare for a potentially devastating global pandemic of an infectious disease. Initial concern was focused on …H5N1…. More recently…a devastating outbreak of Ebola virus..(and) several other emerging viruses are believed to seriously threaten global health and global security. To prepare, scientists have been urged to discover new vaccines and treatments for these emerging viruses. At the same time, political leaders have been urged by global health experts to invest millions in a “top down” restructuring of the global health system. This article takes a different view. It focuses on an alternative approach to the scientific discovery of treatments for individual patients, reviews the mechanisms of action and clinical experience with specific drugs that might be useful, and considers whether or not recent lessons regarding this “bottom up” approach to treatment have been learned”. Now with a new virus and pandemic upon us, Fedson's 2016 comments appear chilling, are cause for reflection on what we have learnt and importantly offer focus on an immediate opportunity in the area of treating the host (Fedson DS, Ann Transl Med, 2016;4:421). Refereed/Peer-reviewed

Objectives: To estimate the pancreatic cancer risk among subjects exposed versus not exposed to proton pump inhibitors.Methods: The authors searched PubMed, EMBASE, Scopus, Cochrane Library, and clinicaltrials.gov to identify relevant studies. The authors quantified pancreatic cancer risk among subjects exposed versus not exposed to PPIs, expressed as the pooled (adjusted) odds ratio (OR/aOR) and 95% confidence interval (95%CI) in overall and sensitivity analyses.Results: One randomized trial, two cohort, four case-control, and five nested case-control studies with 700,178 subjects (73,985 cases; 626,193 controls) were retained. PPI exposure was associated with pancreatic cancer risk (OR = 1.75, 95%CI = 1.12-2.72, I2 = 99%); confirmed in sensitivity analyses for high-quality studies, observational studies, case-control studies, studies with pancreatic cancer as the primary outcome, and in sensitivity analyses for diabetes and obesity but not for pancreatitis and smoking. This association was independent of the duration and Defined Daily Dose of PPI exposure. Rabeprazole had a singular significant association with pancreatic cancer (OR = 5.40, 95%CI = 1.98-14.703, I2 = 87.9%).Conclusion: The class of PPIs is associated with a 1.75-fold increase in pancreatic cancer risk, confirmed in sensitivity analyses.

Cancer medicine is a challenging field with an increasing range of promising therapies and combinations. Increasingly, personalised medicine shows promise to improve cancer outcomes – response, symptom control, survival and cure. However, optimal dosing is an under‐appreciated aspect of personalised anticancer therapy, with few clinical trials addressing this specific issue. This position paper aims to inform various health professionals about the principles that guide anticancer drug dose selection and modifications. We discuss the available evidence base for personalised dosing, as well as the professional judgement required by experienced oncology physicians to determine the most appropriate dose for each patient. We provide nine steps to guide clinicians and trainees in this process, based on: pharmacology of each agent (absorption, distribution, metabolism, elimination and mechanism of action); scientific evidence for recommended doses; professional knowledge of patients' unique phenotype (adiposity, comorbidities, etc.); previous drug tolerance; individual dose adjustment in combination therapy; communication and documentation, with the added need for ongoing monitoring and adjustment. We strongly propose professional education and future research towards optimal dosing.

Background Investigations of the associations with colorectal cancer have yielded conflicting results. The aim of our study was to synthesize the research on colorectal cancer risks in BRCA mutation carriers by means of a systematic review and quantitatively by means of meta-analyses overall and in subgroups of BRCA mutation carriers. Methods We searched PubMed/MEDLINE, Embase, Cochrane, Scopus, and ProQuest Dissertation & Theses. Unadjusted odds ratios (ORs) were used to derive pooled estimates of colorectal cancer risk overall and in subgroups defined by mutation type (BRCA1 or BRCA2), cancer type (colorectal or colon cancer), study design (age-sex-adjusted or crude), and ascertainment method (ascertained or inferred genotyping). The associations were evaluated using random-effect models. All statistical tests were two-sided. Results Eighteen studies were included in the systematic review: five cohort studies with ascertained BRCA mutation, six cohort studies involving pedigree analysis, five case-control studies, and two kin-cohort studies. Of these, 14 were used in the meta-analysis, which revealed a statistically significant increased risk of colorectal cancer in overall BRCA mutation carriers (OR = 1.24, 95% confidence interval (CI) = 1.02 to 1.51, P = .03). In subgroup meta-analyses by BRCA type, BRCA1 mutation was associated with increased risk of colorectal cancer (OR = 1.49, 95% CI = 1.19 to 1.85, P

Background/objective Corticosteroids have long been used to effectively treat rheumatic disorders, but adverse effects associated with extended-duration regimens generate disagreement among clinicians regarding optimal tapering strategies. The objective of this systematic review was to assess clinical outcomes of differing tapering regimens after corticosteroid monotherapy in adults with rheumatic disorders. Methods A systematic review of Medline/PubMed, Embase, Cochrane, International Pharmaceutical Abstracts, Web of Science, Scopus, Global Index Medicus, American College of Rheumatology, gray literature, and reference lists up to June 27, 2018, was conducted by 2 authors. Randomized controlled trials, case-control studies, and prospective observational studies comparing at least 2 tapering strategies of medium- to high-dose (>7.5 mg but ≤100 mg oral prednisone equivalent daily), extended-duration (≥10 days) corticosteroids were included if they reported at least 1 efficacy and 1 adverse effect parameter. Results Two studies met criteria for the review, which included 62 patients. One study examined a prednisolone versus a modified release prednisone taper for giant cell arteritis and suggested 80% (n = 4) and 85.7% (n = 6) remission rates, respectively, at 26 weeks. The other study examined a methylprednisolone versus a prednisone taper for polymyalgia rheumatica and reported 100% and 89% remission rates, respectively, at 26 weeks. Adverse effects reported between the 2 studies included sleep, hyperglycemia, infection, and fractures. However, the studies were not powered to detect differences in these outcomes. Conclusions There is no high-level evidence to guide tapering until discontinuation after extended courses of medium- to high-dose treatment regimens, as current guidelines rely heavily on expert opinion and small case series with a trial-and-error approach. This review supports the need for additional research to shift tapering recommendations to a more evidence-based practice.

For many cancers, adolescents and young adults (AYA) have worse outcomes than for children and adults. Many factors may contribute to the AYA survival gap, including differences in biology, therapeutic intent, and adherence to therapy. It has been observed that male AYAs have poorer outcomes than females. The purpose of this work was to test the proposition that gender-related pharmacologic factors may account for a component of the AYA survival gap. A prospective, multi-institutional pharmacologic study of 79 patients in total with chemosensitive cancers (Ewing sarcoma, osteosarcoma and Hodgkin lymphoma) was conducted, with conventional doxorubicin treatment. Pharmacokinetic data of 13 children, 40 AYAs and 13 adults were valid for analysis. Population pharmacokinetics models were developed for doxorubicin and its metabolite doxorubicinol based on the data created in this study. Consequently, model-based analysis was conducted to investigate the relevant topics. The clearance of doxorubicinol (normalized to body surface area), the main active metabolite of doxorubicin, appears faster in male AYAs than female (p = 0.04, 95% CI 0.1–3.9 L/h). The exposure of doxorubicinol (normalized to dose) is lower in male AYA than female (p = 0.03, 95% CI − 0.005 to − 0.0002 h/L). These might be correlated to the observed difference on nadir neutrophil count between male AYA and female (p = 0.027, 95% CI 0.09–1.4). Gender-related differences in doxorubicin pharmacology may account for worse outcomes for male AYAs with chemosensitive cancers compared to females. These findings may reduce the AYA survival gap compared to other age groups.

Objective To examine the laxative prescriptions in hospital inpatients with cancer and non-cancer pain on oxycodone compared to oxycodone plus naloxone combination. Design Retrospective case note review. Setting A palliative care inpatient unit and a general medical ward in a large tertiary referral hospital. Participants Eighty-four patients receiving oxycodone or combination oxycodone/naloxone on general medical (45 patients) and palliative care wards (39 patients). Main outcome measures The primary recorded outcomes were regular opioid dose (milligrams per day) and number of prescribed laxatives (type, doses, and frequency per day). Results Sixty-three (75%) patients in the study were on at least one laxative. In the general medicine inpatients, those on combined oxycodone/naloxone received on average 3.7 laxative doses per day compared to the oxycodone patients receiving 1.6 doses a day. In the palliative medicine population, both groups received a similar number of laxatives, despite the oxycodone/naloxone patients being on lower opioid doses. Conclusion This retrospective study of hospital inpatients with cancer and non-cancer pain found that laxative use was not reduced in those on combined oxycodone/naloxone compared to oxycodone alone, suggesting that despite the interpretations of the clinical trials in the phase IV setting, the addition of naloxone had no effect on reducing laxative use.

Objective: Depression is a global and growing health issue. Complementary and alternative medicines (CAM) use is common among people with depression. We examined the baseline use of CAM (products, not services) in centrally obese adults with depression, a specific and increasingly important population who were part of a trial of Tai Chi and Qigong for depression. Methods: Self-reported use of CAM products (four major groups: vitamins, herbal medicines, mineral supplements and purified chemicals as nutritional supplements) together with demographic, lifestyle and health status characteristics were collected using validated questions within a written survey. We used descriptive statistics to understand patterns of use. Results: Two hundred and sixty patients participated in the assessment. Half of the patients stated they were using CAM, on average reporting 2.3 CAM per patient. Women were more likely than men, and older people (>60 years) more likely than younger people (

Pharmacovigilance is the detection and assessment of adverse events related to any drug used in clinical practice. In Australia adverse events can be reported to the Therapeutic Goods Administration. Reports are encouraged, even if the drug is old or the prescriber is only suspicious of an adverse event. Australian information about adverse events can be found online in the Database of Adverse Event Notifications and in the publication Medicine Safety Update. The Therapeutic Goods Administration is currently exploring expedited approval pathways to enable some drugs to reach the market quickly. As there will be limited clinical data about these drugs, postmarketing pharmacovigilance will be of increased importance.

Introduction: Chronic cannabis use has been associated with impaired cognition and elevated psychological symptoms, particularly psychotic-like experiences. While Δ9-tetrahydrocannabinol (THC) is thought to be primarily responsible for these deleterious effects, cannabidiol (CBD) is purported to have antipsychotic properties and to ameliorate cognitive, symptomatic, and brain harms in cannabis users. However, this has never been tested in a prolonged administration trial in otherwise healthy cannabis users. Here, we report the first study of prolonged CBD administration to a community sample of regular cannabis users in a pragmatic trial investigating potential restorative effects of CBD on psychological symptoms and cognition. Materials and Methods: Twenty frequent cannabis users (16 male, median age 25 years) underwent a 10-week open-label trial of 200 mg of daily oral CBD treatment, while continuing to use cannabis as usual. The majority of participants were daily cannabis users who had used cannabis for several years (median 5.5 years of regular use). Participants underwent psychological and cognitive assessments at baseline (BL) and post-treatment (PT) and were monitored weekly throughout the trial. Results: CBD was well tolerated with no reported side effects; however, participants retrospectively reported reduced euphoria when smoking cannabis. No impairments to cognition were found, nor were there deleterious effects on psychological function. Importantly, participants reported significantly fewer depressive and psychotic-like symptoms at PT relative to BL, and exhibited improvements in attentional switching, verbal learning, and memory. Increased plasma CBD concentrations were associated with improvements in attentional control and beneficial changes in psychological symptoms. Greater benefits were observed in dependent than in nondependent cannabis users. Conclusions: Prolonged CBD treatment appears to have promising therapeutic effects for improving psychological symptoms and cognition in regular cannabis users. Our findings require replication given the lack of a placebo control in this pragmatic trial, but suggest that CBD may be a useful adjunct treatment for cannabis dependence.

Background In many health settings, administration of medicinal cannabis poses significant implementation barriers including drug storage and safety for administering staff and surrounding patients. Different modes of administration also provide different yet potentially significant issues. One route that has become of clinical interest owing to the rapid onset of action and patient control of the inhaled amount (via breath timing and depth) is that of vaporisation of cannabinoid products. Although requiring a registered therapeutic device for administration, this is a relatively safe method of intrapulmonary administration that may be particularly useful for patients with difficulty swallowing, and for those in whom higher concentrations of cannabinoids are needed quickly. A particular concern expressed to researchers undertaking clinical trials in the hospital is that other patients, nurses, and clinical or research staff may be exposed to second-hand vapours in the course of administering vaporised products to patients. Objective The objective of this study was to take samples from two research staff involved in administering vaporised Δ9-tetrahydrocannabinol to participants in a clinical trial, to examine and quantitate cannabinoid presence. Methods Blood samples from two research staff were taken during the exposure period for three participants (cannabis users) over the course of approximately 2.5 h and analysed using tandem mass spectrometry. Results Blood samples taken over a vaporised period revealed exposure below the limit of detection for Δ9-tetrahydrocannabinol and two metabolites, using tandem mass spectrometry analytical methods. Conclusions These results are reassuring for hospital and clinical trial practices with staff administering vaporised cannabinoid products, and helpful to ethics committees wishing to quantify risk.

AIMS: This prospective, randomized study was initiated to assess the impact of pharmacokinetically (PK)‐guided paclitaxel (PTX) dosing on toxicity and efficacy compared with body‐surface area (BSA)‐based dosing in Chinese non‐small cell lung cancer patients. METHODS: A total of 319 stage IIIB/IV non‐small cell lung cancer patients receiving first‐line chemotherapy were enrolled. Patients were randomized to receive 3‐weekly carboplatin plus PTX at a starting dose of 175 mg/m(2) with subsequent PTX dosing based on either BSA or PK‐guided dosing targeting time above a PTX plasma concentration of 0.05 μmol/L (PTX(Tc > 0.05)) between 26 and 31 hours. The primary safety endpoint was grade 4 haematological toxicity. The secondary endpoints were neuropathy, objective response rate, progression‐free survival and overall survival. RESULTS: In total, 275 (86%) patients completed ≥2 cycles of chemotherapy (140 in BSA arm and 135 in PK arm). In cycle 1, with the same PTX dose, average PTX(Tc > 0.05) was 37 hours (range = 18–57 hours). Over cycles 2–4, patients in the PK arm had significantly lower average PTX doses and exposure compared with the BSA arm (128 vs 161 mg/m(2), P < .0001 and 29 vs 35 hours, P < .0001). PK‐guided dosing significantly reduced the cumulative incidence of grade 4 haematological toxicity (15% vs 24%, P = .004), grade 4 neutropenia (15% vs 23%, P = .009) and grade ≥ 2 neuropathy (8% vs 21%, P = .005). Objective response rate (32% vs 26%, P = .28) and overall survival (21.0 vs 24.0 months, P = .815) were similar in PK and BSA arms. Progression‐free survival was slightly improved in PK arm (4.67 vs 4.17 months, P = .026). CONCLUSION: PK‐guided PTX dosing significantly reduced grade 4 haematological toxicities and grade ≥ 2 neuropathy without an adverse impact on clinical outcomes.