Opioid analgesia for acute low back pain and neck pain (the OPAL trial): a randomised placebo-controlled trial.

BACKGROUND: Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. METHODS: OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone-naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). FINDINGS: Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI -0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). INTERPRETATION: Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. FUNDING: National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and SafeWork SA.

Geographic variation in sodium-glucose cotransporter 2 inhibitor and glucagon-like peptide-1 receptor agonist use in people with type 2 diabetes in New South Wales, Australia.

AIM: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and cardio-renal outcomes for people with type 2 diabetes (T2D). However, geographic and socio-economic variation in use is not well understood. METHODS: We identified 367 829 New South Wales residents aged ≥40 years who dispensed metformin in 2020 as a proxy for T2D. We estimated the prevalence of use of other glucose-lowering medicines among people with T2D and the prevalence of SGLT2i and GLP-1RA use among people using concomitant T2D therapy (i.e. metformin + another glucose-lowering medicine). We measured the prevalence by small-level geography, stratified by age group, and characterized by remoteness and socio-economic status. RESULTS: The prevalence of SGLT2i (29.7%) and GLP-1RA (8.3%) use in people with T2D aged 40-64 increased with geographic remoteness and in areas of greater socio-economic disadvantage, similar to other glucose-lowering medicines. The prevalence of SGLT2i (55.4%) and GLP-1RA (15.4%) among people using concomitant T2D therapy varied across geographic areas, with lower SGLT2i use in more disadvantaged areas and localized areas of high GLP-1RA use (2.5 times the median). Compared with people aged 40-64 years, the prevalence of SGLT2i and GLP-1RA use was lower in older age groups, but with similar patterns of variation across geographic areas. CONCLUSIONS: The prevalence of SGLT2i and GLP-1RA use varied by geography, probably reflecting a combination of system- and prescriber-level factors. Socio-economic variation in GLP-1RA use was overshadowed by localized patterns of prescribing. Continued monitoring of variation can help shape interventions to optimize use among people who would benefit the most.

Estimation of adherence to urate-lowering therapy in people living with gout using Australia's Pharmaceutical Benefits Scheme and patient-reported dosing.

AIMS: The aim of this study was to estimate adherence to urate-lowering therapy (ULT), predominately allopurinol, from Australia's Pharmaceutical Benefits Scheme (PBS) claims database in association with (1) patient-reported doses and (2) World Health Organization's (WHO) defined daily doses (DDD), namely, allopurinol (400 mg/day) or febuxostat (80 mg/day). METHODS: Proportion of days covered (PDC) was calculated in 108 Gout App (Gout APP) trial participants with at least two recorded ULT dispensings in an approximately 12-month period before provision of intervention or control apps. Adherence was defined as PDC ≥80%. We measured the correlation between the two methods of calculating PDC using a Wilcoxon signed rank test. Agreement between ULT-taking status (self-reports) and ULT-dispensed status (PBS records) was tested with Cohen's kappa (κ), and positive and negative percent agreement. RESULTS: Allopurinol was prescribed in 93.5% of participants taking ULT. Their self-reported mean daily dose (SD) was 291 (167) mg/day. Mean PDC (SD) for allopurinol was 83% (21%) calculated using self-reported dose, and 63% (24%) using WHO's DDD. Sixty-three percent of allopurinol users were identified as adherent (PDC ≥80%) using self-reported dose. There was good agreement between self-reported ULT use and PBS dispensing claims (κ = 0.708, P < .001; positive percent agreement = 90%, negative percent agreement = 82%). CONCLUSIONS: Participant-reported allopurinol daily doses, in addition to PBS dispensing claims, may enhance confidence in estimating PDC and adherence compared to using DDD. This approach improves adherence estimations from pharmaceutical claims datasets for medications where daily doses vary between individuals or where there is a wide therapeutic dose range.

Evaluation of Published Population Pharmacokinetic Models to Inform Tacrolimus Therapy in Adult Lung Transplant Recipients.

BACKGROUND: The applicability of currently available tacrolimus population pharmacokinetic models in guiding dosing for lung transplant recipients is unclear. In this study, the predictive performance of relevant tacrolimus population pharmacokinetic models was evaluated for adult lung transplant recipients. METHODS: Data from 43 lung transplant recipients (1021 tacrolimus concentrations) administered an immediate-release oral formulation of tacrolimus were used to evaluate the predictive performance of 17 published population pharmacokinetic models for tacrolimus. Data were collected from immediately after transplantation up to 90 days after transplantation. Model performance was evaluated using (1) prediction-based assessments (bias and imprecision) of individual predicted tacrolimus concentrations at the fourth dosing based on 1 to 3 previous dosings and (2) simulation-based assessment (prediction-corrected visual predictive check; pcVPC). Both assessments were stratified based on concomitant azole antifungal use. Model performance was clinically acceptable if the bias was within ±20%, imprecision was ≤20%, and the 95% confidence interval of bias crossed zero. RESULTS: In the presence of concomitant antifungal therapy, no model showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33), and pcVPC plots displayed poor model fit to the data set. However, this fit slightly improved in the absence of azole antifungal use, where 4 models showed acceptable performance in predicting tacrolimus concentrations at the fourth dosing (n = 33). CONCLUSIONS: Although none of the evaluated models were appropriate in guiding tacrolimus dosing in lung transplant recipients receiving concomitant azole antifungal therapy, 4 of these models displayed potential applicability in guiding dosing in recipients not receiving concomitant azole antifungal therapy. However, further model refinement is required before the widespread implementation of such models in clinical practice.

'We are somehow fixated on this being a diabetes drug': a qualitative study exploring the views of cardiologists and nephrologists about sodium-glucose cotransporter 2 inhibitor initiation.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now indicated for heart failure and chronic kidney disease (CKD), irrespective of the presence of diabetes. Hence, cardiologists and nephrologists have an important role in initiating these drugs. AIMS: To explore cardiologists' and nephrologists' perspectives regarding initiating SGLT2i and their safety monitoring practices when initiating SGLT2i. METHODS: Purposive and snowball approaches were used to recruit participants working in diverse areas in New South Wales, Australia. Semi-structured interviews were conducted with 12 cardiologists and 12 nephrologists. Interviews were conducted until thematic saturation was reached. Emergent themes were identified from transcripts. An iterative general inductive approach was used for data analysis. RESULTS: There was a reluctance amongst most non-heart-failure subspecialist cardiologists to initiate SGLT2i. Reasons included the perception of SGLT2i as diabetes drugs, concern about side effects, lack of experience and issues with follow-up. In contrast, nephrologists reported feeling confident to initiate SGLT2i. Nephrologists varied in their opinions about the severity of CKD at which SGLT2i initiation was reasonable and monitoring of renal function following initiation. Government subsidisation was an important factor in the decision to prescribe SGLT2i to people without diabetes. CONCLUSIONS: Our findings highlight the complex transition from the perception of SGLT2i as diabetes drugs to cardiometabolic and reno-protective agents. Interdisciplinary collaboration may enable greater confidence amongst specialists to initiate SGLT2i, including in patients with CKD. Additionally, there is a need for clear and detailed guidance about SGLT2i prescription in patients with renal dysfunction and renal function monitoring following SGLT2i initiation.

The experiences and perspectives of people with gout on urate self-monitoring.

INTRODUCTION: Gout management remains suboptimal despite safe and effective urate-lowering therapy. Self-monitoring of urate may improve gout management, however, the acceptability of urate self-monitoring by people with gout is unknown. The aim of this study was to explore the experiences of urate self-monitoring in people with gout. METHODS: Semistructured interviews were conducted with people taking urate-lowering therapy (N = 30) in a 12-month trial of urate self-monitoring in rural and urban Australia. Interviews covered the experience of monitoring and its effect on gout self-management. Deidentified transcripts were analysed thematically. RESULTS: Participants valued the ability to self-monitor and gain more understanding of urate control compared with the annual monitoring ordered by their doctors. Participants indicated that self-monitoring at home was easy, convenient and informed gout self-management behaviours such as dietary modifications, hydration, exercise and medication routines. Many participants self-monitored to understand urate concentration changes in response to feeling a gout flare was imminent or whether their behaviours, for example, alcohol intake, increased the risk of a gout flare. Urate concentrations were shared with doctors mainly when they were above target to seek management support, and this led to allopurinol dose increases in some cases. CONCLUSION: Urate self-monitoring was viewed by people with gout as convenient and useful for independent management of gout. They believed self-monitoring achieved better gout control with a less restricted lifestyle. Urate data was shared with doctors at the patient's discretion and helped inform clinical decisions, such as allopurinol dose changes. Further research on implementing urate self-monitoring in routine care would enable an evaluation of its impact on medication adherence and clinical outcomes, as well as inform gout management guidelines. PATIENT OR PUBLIC CONTRIBUTION: One person with gout, who was not a participant, was involved in the study design by providing feedback and pilot testing the semistructured interview guide. In response to their feedback, subsequent modifications to the interview guide were made to improve the understandability of the questions from a patient perspective. No additional questions were suggested.

Effects of Allopurinol on the Progression of Chronic Kidney Disease.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHODS: In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin:creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULTS: Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin:creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSIONS: In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment with allopurinol did not slow the decline in eGFR as compared with placebo. (Funded by the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand; CKD-FIX Australian New Zealand Clinical Trials Registry number, ACTRN12611000791932.).

Patient factors and health outcomes associated with illness perceptions in people with gout.

OBJECTIVE: Illness perceptions are views and beliefs formed in response to a health threat which may influence self-management behaviours and chronic disease outcomes. Despite effective medication, sub-optimal outcomes in gout are common. This study aimed to quantitatively investigate illness perceptions in gout to examine how illness perceptions relate to health outcomes. METHODS: Data were obtained from a randomised-controlled trial where people with gout (n = 493) completed surveys measuring illness perceptions (Brief Illness Perception Questionnaire (B-IPQ)), gout flares, medication adherence, health-related quality of life, healthcare utilisation and productivity, alongside serum urate blood tests at baseline, 6- and 12-month follow-ups. Multivariable linear regression identified patient factors independently associated with each B-IPQ item score. Logistic and linear regression, adjusted for age and sex, determined whether baseline B-IPQ items could predict current and future health outcomes. RESULTS: Younger individuals and those with severe gout were more likely to experience pessimistic illness perceptions at baseline. Optimistic illness perceptions were associated with lower odds of having at least one flare in the preceding 6 months. Every 1-point increase in B-IPQ treatment control, indicating the optimistic view that gout is treatable, decreased the odds of a recent flare prior to baseline by 33% (OR : 0.67; 95%CI : 0.53,0.85; p< 0.001) and prior to 12-month follow-up by 15% (OR : 0.85; 95%CI : 0.76,0.96; p= 0.01). Pessimistic illness perceptions also predicted poorer medication adherence, health-related quality of life and productivity but not serum urate levels. CONCLUSION: Modifying pessimistic illness perceptions, including, but not limited to, patient education, may promote prudent self-management behaviours and better outcomes in gout. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry; https://www.anzctr.org.au/; ACTRN12616000455460.

Blood, dose recommendation reports and phone calls: Experiences of a therapeutic drug monitoring advisory service for vancomycin.

Dose-prediction software is recommended to enable area under the curve over 24 h (AUC24 )-guided dosing of the antibiotic vancomycin. However, uncertainty remains about how best to implement software in the clinic. We describe the activity, over 18 months, of a consultative therapeutic drug monitoring Advisory Service (the Service) for vancomycin that used dose-prediction software alongside clinical expertise, identifying factors that influence attainment of therapeutic targets. Of the 408 vancomycin dose reports provided for 182 courses of therapy, most (57%) recommended a dose change. The majority (82.8%, 193/233) of recommended dose adjustments were accepted by treating teams. A dose report was not published for 125 courses of therapy, with reasons including patient in intensive care unit or service error. An estimated 26.6 h of staff time was allocated to Service activities each month. Publication of a dose report facilitated attainment of therapeutic targets (P = .002). Software integration could improve Service outcomes, avoiding errors and reducing staff workload.

Optimizing adherence to allopurinol for gout: patients' perspectives.

AIMS: Poor adherence to allopurinol among people with gout contributes to suboptimal gout management. This study sought to understand the facilitators and barriers to allopurinol adherence across the three stages of medication adherence, and patient perspectives on strategies to improve adherence, including self-monitoring urate concentration. METHODS: Semi-structured interviews were conducted with 26 people with gout, previously or currently taking allopurinol. De-identified verbatim transcripts were thematically analysed using an inductive and deductive approach. RESULTS: Facilitators of adherence during allopurinol initiation were motivation to prevent gout flares and trust in the advice of their healthcare professionals (HCPs). Reluctance to commence long-term medication was a barrier to allopurinol initiation. Believing in the effectiveness and necessity of allopurinol and reminder systems were facilitators of implementation. Barriers to implementation included forgetfulness, gout flares and limited feedback on allopurinol's effectiveness. Patients discontinued therapy when allopurinol was perceived as ineffective or unnecessary. Discontinuation coincided with patients experiencing gout flares while adhering to allopurinol and receiving suboptimal advice about gout management. Patients identified receiving accurate advice from HCPs and regular urate monitoring for feedback on allopurinol's effectiveness as potential strategies to improve adherence. Perceived benefits of self-monitoring urate as a strategy to promote adherence included the ability to self-manage gout and make informed decisions about allopurinol therapy with their HCP. CONCLUSION: Patient perceptions of the effectiveness and necessity of allopurinol influenced intentional adherence during medication initiation, implementation and discontinuation. Strategies that inform patients of their urate control and provide accurate medical advice have the potential to improve adherence to allopurinol.

Adaptation of a population pharmacokinetic model to inform tacrolimus therapy in heart transplant recipients.

AIM: Existing tacrolimus population pharmacokinetic models are unsuitable for guiding tacrolimus dosing in heart transplant recipients. This study aimed to develop and evaluate a population pharmacokinetic model for tacrolimus in heart transplant recipients that considers the tacrolimus-azole antifungal interaction. METHODS: Data from heart transplant recipients (n = 87) administered the oral immediate-release formulation of tacrolimus (Prograf®) were collected. Routine drug monitoring data, principally trough concentrations, were used for model building (n = 1099). A published tacrolimus model was used to inform the estimation of Ka , V2 /F, Q/F and V3 /F. The effect of concomitant azole antifungal use on tacrolimus CL/F was quantified. Fat-free mass was implemented as a covariate on CL/F, V2 /F, V3 /F and Q/F on an allometry scale. Subsequently, stepwise covariate modelling was performed. Significant covariates influencing tacrolimus CL/F were included in the final model. Robustness of the final model was confirmed using prediction-corrected visual predictive check (pcVPC). The final model was externally evaluated for prediction of tacrolimus concentrations of the fourth dosing occasion (n = 87) from one to three prior dosing occasions. RESULTS: Concomitant azole antifungal therapy reduced tacrolimus CL/F by 80%. Haematocrit (∆OFV = -44, P < .001) was included in the final model. The pcVPC of the final model displayed good model adequacy. One recent drug concentration is sufficient for the model to guide tacrolimus dosing. CONCLUSION: A population pharmacokinetic model that adequately describes tacrolimus pharmacokinetics in heart transplant recipients, considering the tacrolimus-azole antifungal interaction was developed. Prospective evaluation is required to assess its clinical utility to improve patient outcomes.

The safe use of metformin in heart failure patients both with and without T2DM: A cross-sectional and longitudinal study.

AIMS: This study investigated the safe use of metformin in patients with (1) type 2 diabetes mellitus (T2DM) and heart failure on metformin, and (2) heart failure without T2DM and metformin naïve. METHODS: Two prospective studies on heart failure patients were undertaken. The first was a cross-sectional study with two patient cohorts, one with T2DM on metformin (n = 44) and one without T2DM metformin naive (n = 47). The second was a 12-week interventional study of patients without T2DM (n = 27) where metformin (500 mg immediate release, twice daily) was prescribed. Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were compared between cohorts. Univariable and multivariable analysis analysed the effects of variables on plasma lactate concentrations. RESULTS: Plasma metformin and lactate concentrations mostly (99.9%) remained below safety thresholds (5 mg/L and 5 mmol/L, respectively). Metformin concentration had no significant relationship with lactic acidosis safety markers. In the interventional study, New York Heart Association (NYHA) II (P < .03) and III (P < .001) grading was associated with higher plasma lactate concentrations, whereas male sex was associated with 47% higher plasma lactate concentrations (P < .05). The pharmacokinetics of heart failure patients with and without T2DM were similar. CONCLUSIONS: We observed no unsafe plasma lactate concentrations in patients with heart failure treated with metformin. Metformin exposure did not influence plasma lactate concentrations, but NYHA class and sex did. The pharmacokinetics of metformin in heart failure patients are similar irrespective of T2DM. These findings may support the safe use of metformin in heart failure patients with and without T2DM.

Trends in use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in Australia in the era of increased evidence of their cardiovascular benefits (2014-2022).

PURPOSE: To investigate trends in SGLT2i and GLP-1RA use in Australia in the era of increased evidence of their cardiovascular benefits. METHODS: We used national dispensing claims for a 10% random sample of Australians to estimate the number of prevalent and new users (no dispensing in the prior year) of SGLT2i or GLP-1RA per month from January 2014 to July 2022. We assessed prescriber specialty and prior use of other antidiabetic and cardiovascular medicines as a proxy for evidence of type 2 diabetes (T2D) and cardiovascular conditions, respectively. RESULTS: We found a large increase in the number of prevalent users (216-fold for SGLT2i; 11-fold for GLP-1RA); in July 2022 approximately 250,000 Australians were dispensed SGLT2i and 120,000 GLP-1RA. Most new users of SGLT2i or GLP-1RA had evidence of both T2D and cardiovascular conditions, although from 2022 onwards, approximately one in five new users of SGLT2i did not have T2D. The proportion of new users initiating SGLT2i by cardiologists increased after 2021, reaching 10.0% of initiations in July 2022. Among new users with evidence of cardiovascular conditions, empagliflozin was the most commonly prescribed SGLT2i, while dulaglutide or semaglutide was the most common GLP-1RA. CONCLUSION: SGLT2i and GLP-1RA use is increasing in Australia, particularly in populations with higher cardiovascular risk. The increased use of SGLT2i among people without evidence of T2D suggests that best-evidence medicines are adopted in Australia across specialties, aligning with new evidence and expanding indications.

Optimizing the dosing of vancomycin in patients receiving intermittent haemodialysis with low-flux filters, and the potential impact of dosing software.

AIM: Iterative approaches to vancomycin dosing (e.g., dosing when trough concentrations <15-20 mg/L) can be inadequate. Computer-guided dosing may be superior but has not been evaluated in patients with kidney failure receiving replacement therapy. We evaluated vancomycin concentrations using a hospital protocol and a pharmacokinetic software. We measured vancomycin clearance by the FX8 low-flux filter because data are absent. METHODS: We retrospectively reviewed records of adults with kidney failure requiring replacement therapy receiving vancomycin and dialysed with the FX8 low-flux filter, and calculated the proportion of pre-dialysis concentrations that were within, above or below a specified range. One and two-compartment models in the pharmacokinetic software were assessed by computing mean prediction error (MPE) and root mean square error (RMSE) of observed versus predicted concentrations. Vancomycin extracorporeal clearance was prospectively determined using the extraction method. RESULTS: In 24 patients (34 courses; 139 paired observed and predicted concentrations), 62/139 (45%) pre-dialysis concentrations were 15-25 mg/L, 29/139 (21%) were above, and 48/139 (35%) were below. MPE for the one-compartment model was -0.2 mg/L, RMSE 5.3 mg/L. MPE for the two-compartment model was 2.0 mg/L, RMSE 5.6 mg/L. Excluding the first paired concentrations, the subsequent MPE (n = 105) using one-compartment model was -0.5 mg/L, RMSE 5.6 mg/L. The MPE for the two-compartment model was 2.1 mg/L, RMSE 5.8 mg/L. The median extracorporeal clearance was 70.7 mL/min (range: 10.3-130.3; n = 22). CONCLUSIONS: Vancomycin dosing was suboptimal and the pharmacokinetic software was not sufficiently predictive. These may improve with a loading dose. The substantial removal of vancomycin by low-flux filters is not accounted for by the models tested.

Ongoing challenges of off-label prescribing.

Off-label prescribing refers to prescribing that is not concordant with the indications, doses, routes of administration or patient groups included in the Australian approved product information. Off-label prescribing is common, especially for vulnerable patient groups who tend to be excluded from clinical trials, such as children and pregnant women. There may be increased risk of prescriber liability if the patient experiences an adverse event following off-label prescription, particularly when supporting evidence or guidelines are lacking. There may be additional costs to the patient if the medicine is not subsidised for the off-label indication. Prescribers should ensure patients are aware when a medicine is being prescribed off label, and informed of potential benefits and harms. Alternative pathways for approval of new indications, doses and patient groups may reduce the need for off-label prescribing.

Immunomodulatory effects of pharmaceutical opioids and antipyretic analgesics: Mechanisms and relevance to infection.

Understanding how pharmaceutical opioids and antipyretic analgesics interact with the immune system potentially has major clinical implications for management of patients with infectious diseases and surgical and critical care patients. An electronic search was carried out on MEDLINE, EMBASE, PsycINFO, CENTRAL and the Cochrane library to identify reports describing the immunomodulatory effects of opioid analgesics and antipyretic analgesics, and their effects in infectious diseases. In adaptive immunity, nonsteroidal anti-inflammatory drugs have divergent effects: augmenting cell-mediated immunity but inhibiting humoral immunity. Nonsteroidal anti-inflammatory drugs have demonstrated a beneficial role in Mycobacterium tuberculosis infection and histoplasmosis in animals, and may be plausible adjuvants to antimicrobial agents in these diseases. There is a need to evaluate these findings rigorously in human clinical trials. There is preliminary evidence demonstrating antiviral effects of indomethacin in SARS CoV-2 in vitro; however, uncertainty regarding its clinical benefit in humans needs to be resolved in large clinical trials. Certain opioid analgesics are associated with immunosuppressive effects, with a developing understanding that fentanyl, morphine, methadone and buprenorphine suppress innate immunity, whilst having diverse effects on adaptive immunity. Morphine suppresses key cells of the innate immunity and is associated with greater risk of infection in the postsurgical setting. Efforts are needed to achieve adequate analgesia whilst avoiding suppression of the innate immunity in the immediate postoperative period caused by certain opioids, particularly in cancer surgery.

Evaluation of published population pharmacokinetic models to inform tacrolimus dosing in adult heart transplant recipients.

BACKGROUND AND AIM: Identification of the most appropriate population pharmacokinetic model-based Bayesian estimation is required prior to its implementation in routine clinical practice to inform tacrolimus dosing decisions. This study aimed to determine the predictive performances of relevant population pharmacokinetic models of tacrolimus developed from various solid organ transplant recipient populations in adult heart transplant recipients, stratified based on concomitant azole antifungal use. Concomitant azole antifungal therapy alters tacrolimus pharmacokinetics substantially, necessitating dose adjustments. METHODS: Population pharmacokinetic models of tacrolimus were selected (n = 17) for evaluation from a recent systematic review. The models were transcribed and implemented in NONMEM version 7.4.3. Data from 85 heart transplant recipients (2387 tacrolimus concentrations) administered the oral immediate-release formulation of tacrolimus (Prograf) were obtained up to 391 days post-transplant. The performance of each model was evaluated using: (i) prediction-based assessment (bias and imprecision) of the individual predicted tacrolimus concentration of the fourth dosing occasion (MAXEVAL = 0, FOCE-I) from 1-3 prior dosing occasions; and (ii) simulation-based assessment (prediction-corrected visual predictive check). Both assessments were stratified based on concomitant azole antifungal use. RESULTS: Regardless of the number of prior dosing occasions (1-3) and concomitant azole antifungal use, all models demonstrated unacceptable individual predicted tacrolimus concentration of the fourth dosing occasion (n = 152). The prediction-corrected visual predictive check graphics indicated that these models inadequately predicted observed tacrolimus concentrations. CONCLUSION: All models evaluated were unable to adequately describe tacrolimus pharmacokinetics in adult heart transplant recipients included in this study. Further work is required to describe tacrolimus pharmacokinetics for our heart transplant recipient cohort.

Population pharmacokinetic modelling of febuxostat in healthy subjects and people with gout.

AIMS: To investigate and characterise the pharmacokinetics of febuxostat and the effect of the covariates of renal function and body size descriptors on the pharmacokinetics of the drug. METHODS: Blood samples (n = 239) were collected using sparse and rich sampling strategies from healthy (n = 9) and gouty (n = 29) subjects. Febuxostat plasma concentrations were measured by a validated high-performance liquid chromatography method. Population pharmacokinetic analysis was performed using NONMEM. A common variability on bioavailability (FVAR) approach was used to test the effect of fed status on absorption parameters. Covariates were modelled using a power model. RESULTS: The time course of the plasma concentrations of febuxostat is best described by a two-compartment model. In the final model, the population mean for apparent clearance (CL/F), apparent central volume of distribution (Vc/F), apparent peripheral volume of distribution (Vp/F), absorption rate constant (ka) and apparent intercompartmental clearance (Q/F) were 6.91 l h-1 , 32.8 l, 19.4 l, 3.6 h-1 and 1.25 l h-1 , respectively. The population parmater variability (coefficient of variation) for CL/F, Vc/F and Vp/F were 13.6, 22 and 19.5%, respectively. Food reduced the relative biovailability and ka by 67% and 87%, respectively. Renal function, as assessed by creatinine clearance, was a significant covariate for CL/F while body mass index was a significant covariate for Vc/F. CONCLUSIONS: Renal function and body mass index were significant covariates. Further work is warranted to investigate the clinical relevance of these results, notably as renal impairment and obesity are common occurrences in people with gout.

Persistence with urate-lowering therapy in Australia: A longitudinal analysis of allopurinol prescriptions.

AIM: Gout is the most common form of inflammatory arthritis in men. Despite the availability of effective urate-lowering therapies (ULT), the management of gout is suboptimal due to poor persistence with ULT. This study examined national prescribing patterns of ULT to determine persistence with allopurinol in Australia. METHODS: A 10% sample of the Australian Pharmaceutical Benefits Scheme dispensing claims database was used to identify individuals initiated on allopurinol between April 2014 and December 2019. The number of allopurinol scripts dispensed was used to estimate persistence with allopurinol. Persistence was defined as the number of months from initiation until discontinuation (last prescription with no further scripts acquired for a period thereafter). Kaplan-Meier curves were used to examine persistence, while Cox regression analysis was used to examine the influence of gender, concomitant colchicine and age. RESULTS: The largest drop in persistence occurred immediately after initiation, with 34% of patients discontinuing allopurinol 300-mg therapy in the first month. Median persistence with allopurinol 300 mg was 5 months (95% confidence interval 4.76-5.24), with around 63% of individuals not persisting with this therapy for more than 12 months. Concomitant prescription of colchicine on the day of allopurinol initiation only occurred in 7% of allopurinol initiations. No increase in persistence was observed for those co-prescribed colchicine. CONCLUSION: Persistence with allopurinol was poor. More effective methods targeting prescribers, patients and systems are required to promote persistence with allopurinol. Improving persistence to allopurinol is an important public health goal given the proven potential of this medication to eliminate gout.

Emerging therapeutic drug monitoring of anti-infective agents in Australian hospitals: Availability, performance and barriers to implementation.

AIMS: The purpose of the study was to assess the status of emerging therapeutic drug monitoring (TDM) of anti-infective agents in Australian hospitals. METHODS: A nationwide cross-sectional survey of all Australian hospitals operating in the public and private health sector was conducted between August and September 2019. The survey consisted of questions regarding institutional TDM practice for anti-infective agents and clinical vignettes specific to ß-lactam antibiotics. RESULTS: Responses were received from 82 unique institutions, representing all Australian states and territories. All 29 (100%) of principal referral (major) hospitals in Australia participated. Five surveys were partially complete. Only 25% (20/80) of hospitals had TDM testing available on-site for any of the eight emerging TDM candidates considered: ß-lactam antibiotics, anti-tuberculous agents, flucytosine, fluoroquinolones, ganciclovir, human immunodeficiency virus (HIV) drugs, linezolid and teicoplanin. A considerable time lag was noted between TDM sampling and reporting of results. With respect to ß-lactam antibiotic TDM, variable indications, pharmacodynamic targets and sampling times were identified. The three greatest barriers to local TDM performance were found to be (1) lack of timely assays/results, (2) lack of institutional-wide expertise and/or training and (3) lack of guidelines to inform ordering of TDM and interpretation of results. The majority of respondents favoured establishing national TDM guidelines and increasing access to dose prediction software, at rates of 89% and 96%, respectively. CONCLUSION: Translating emerging TDM evidence into daily clinical practice is slow. Concerted efforts are required to address the barriers identified and facilitate the implementation of standardised practice.