Showing papers in "British Journal of Clinical Pharmacology in 2021"

Recent developments of HDAC inhibitors: Emerging indications and novel molecules.

Abstract: The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising.

Hypophosphataemia after treatment of iron deficiency with intravenous ferric carboxymaltose or iron isomaltoside-a systematic review and meta-analysis.

Abstract: Aims Hypophosphataemia is an increasingly recognized side-effect of ferric carboxymaltose (FCM) and possibly iron isomaltoside/ferric derisomaltose (IIM), which are used to treat iron deficiency. The aim of this study was to determine frequency, severity, duration and risk factors of incident hypophosphataemia after treatment with FCM and IIM. Methods A systematic literature search for articles indexed in EMBASE, PubMed and Web of Science in years 2005-2020 was carried out using the search terms 'ferric carboxymaltose' OR 'iron isomaltoside'. Prospective clinical trials reporting outcomes on hypophosphataemia rate, mean nadir serum phosphate and/or change in mean serum phosphate from baseline were selected. Hypophosphataemia rate and severity were compared for studies on IIM vs. FCM after stratification for chronic kidney disease. Meta-regression analysis was used to investigate risk factors for hypophosphataemia. Results Across the 42 clinical trials included in the meta-analysis, FCM induced a significantly higher incidence of hypophosphataemia than IIM (47%, 95% CI 36-58% vs. 4%, 95% CI 2-5%), and significantly greater mean decreases in serum phosphate (0.40 vs. 0.06 mmol/L). Hypophosphataemia persisted at the end of the study periods (maximum 3 months) in up to 45% of patients treated with FCM. Meta-regression analysis identified low baseline serum ferritin and transferrin saturation, and normal kidney function as significant predictors of hypophosphataemia. Conclusion FCM is associated with a high risk of hypophosphataemia, which does not resolve for at least 3 months in a large proportion of affected patients. More severe iron deficiency and normal kidney function are risk factors for hypophosphataemia.

Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis.

Abstract: Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has been declared a global pandemic and urgent treatment and prevention strategies are needed. Nitazoxanide, an anthelmintic drug has been shown to exhibit in vitro activity against SARS‐CoV‐2. The present study used physiologically‐based pharmacokinetic (PBPK) modelling to inform optimal doses of nitazoxanide capable of maintaining plasma and lung tizoxanide exposures above the reported SARS‐CoV‐2 EC90. Methods A whole‐body PBPK model was validated against available pharmacokinetic data for healthy individuals receiving single and multiple doses between 500–4000 mg with and without food. The validated model was used to predict doses expected to maintain tizoxanide plasma and lung concentrations above the EC90 in >90% of the simulated population. PopDes was used to estimate an optimal sparse sampling strategy for future clinical trials. Results The PBPK model was successfully validated against the reported human pharmacokinetics. The model predicted optimal doses of 1200 mg QID, 1600 mg TID, 2900 mg BID in the fasted state and 700 mg QID, 900 mg TID and 1400 mg BID when given with food. For BID regimens an optimal sparse sampling strategy of 0.25, 1, 3 and 12h post dose was estimated. Conclusion The PBPK model predicted tizoxanide concentrations within doses of nitazoxanide already given to humans previously. The reported dosing strategies provide a rational basis for design of clinical trials with nitazoxanide for the treatment or prevention of SARS‐CoV‐2 infection. A concordant higher dose of nitazoxanide is now planned for investigation in the seamless phase I/IIa AGILE trial (www.agiletrial.net).

Potential role of IL-17 blocking agents in the treatment of severe COVID-19?

Abstract: After the World Health Organisation declared Coronavirus Disease 2019 (COVID-19) a global pandemic on March 11, 2020, it became clear that health professionals worldwide were facing a severe and unprecedented challenge. On March 28, the FDA issued an emergency use authorisation order for use of chloroquine and hydroxychloroquine in COVID-19 patients, and on May 1, 2020, the agency gave the same authorisation for use of remdesivir. Even though different treatment strategies are undergoing evaluation, particularly for severe COVID-19 cases requiring intensive care, the consensus regarding best treatment approach has not yet been reached. Earlier this year, Zhe Xu and colleagues provided a detailed case report of a 50-year-old man with COVID-19 in the Lancet Respiratory Medicine journal. This case is particularly interesting since it provides a detailed day-to-day account of the hospitalisation, laboratory parameters and histological findings in a patient who neither belonged to a very high-risk age group, nor did he have any other comorbidity. The patient's assessment revealed an overactivation of T cells manifested by an increase in the Th17 subset of CD4+ T cells leading to increased production of IL-17 and IL-22 cytokines which in turn caused the cytokine release storm (CRS) with a rapid and severe deterioration of the patient's condition. Pathologic postmortem lung analysis revealed a high number of Th17 lymphocytes in alveolar spaces. Besides the referenced case report, there is emerging body of evidence supporting the role of IL-17 in the pathogenesis of severe COVID-19 disease, including two recent publications reviewing the immune response in patients with COVID-19, that further emphasise the Th17-type cytokine storm in pathogenesis of the disease. Wu and Yang highlighted the Th17 response in CRS of COVID-19 and proposed using fedratinib, a Janus kinase 2 (JAK2) inhibitor which blocks downstream cellular Th17 signalling pathway, in the treatment of CRS of COVID-19 patients. However, in our view, JAK inhibition of intracellular enzymes would also be associated with significant disadvantages entailing unintended and/or off-target effects leading to difficulty in predicting JAK2 inhibitors' biological effects. Since the increase in Th17 CD4+ T cells is also found in several inflammatory diseases, such as in severe plaque psoriasis, we hypothesise that the use of IL-17 blocking agents could be beneficial in the treatment of severe COVID-19 cases. The ligation of IL-17 to IL-17RA initiates activation of transcription factors NFκB, IκBζ, API and C-EBP, which potentiate IL-17– induced transcription of the most potent proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, G-CSF and GM-CSF), chemokines involved in attracting and further recruitment of immune infiltrates (IL-8, CXCL1, CXCL2, CXCL5, CCL2, CCL7 and CCL20), and matrix metalloproteinases involved in tissue damage (MMP1, MMP3, MMP9, MMP12 and MMP13). IL-17 has been demonstrated in blood and affected tissues of patients with COVID-19, and IL-6 levels were significantly increased on Days 2 and 3 of the patient's hospitalisation; thus, IL-17 inhibitors, which block IL-6 and IL-8 secretion from innate immune system, like neutrophils, mast cells, γδ T cells and innate lymphoid cells (ILC3), could prove as safe and effective therapy for severe COVID-19 (Figure 1). A recent study by Liu et al. also revealed an increased IL-6 level as well as increased levels of several other proinflammatory Th1, Th2 and Th17 cytokines (e.g., IL-2, 4, 6, 7, 10, 12 and 17) in patients with severe COVID-19. Blockade of IL-17 alone has been shown as clinically effective in many circumstances and diseases, despite the presence of myriad of proinflammatory cytokines; nevertheless, relevance of mediators crucial for the CRS response remains to be elucidated. IL-17 specifically boosts proinflammatory, but not antiviral gene expression in human cells infected with respiratory viruses by stimulating non immune cells (fibroblasts and epithelial cells) to produce increased amounts of proinflammatory cytokines and chemokines in response to viral infections that attract other immune cell types (for example, neutrophils) which can lead to increased morbidity while simultaneously remaining inefficient in preventing the pathogen's spread. To date, there have been three IL-17 blocking agents available: secukinumab, ixekizumab and brodalumab. Secukinumab and ixekizumab are monoclonal IgG1 antibodies that bind specifically to IL-17A and that have been demonstrated to be very effective in the treatment of severe plaque psoriasis. Both drugs have a quick onset of action, high efficacy, tolerability and a well-established safety profile which does not include a decrease in the lymphocyte count. The substantial decrease in the total number of lymphocytes was found in patients with severe COVID-19, and this seems to facilitate viral replication. In contrast to TNF-α inhibitors, IL-17 blocking agents are not associated with a decrease in lymphocyte count. Brodalumab, a human monoclonal IgG2κ antibody against IL-17 receptor A (IL-17RA), was shown to be superior to placebo and ustekinumab for psoriasis treatment, due to complete blockade of key mediators of theT helper 17 pathway. Brodalumab as an IL-17 receptor blocker could potentially offer improved efficacy; however, patient Received: 12 May 2020 Revised: 7 June 2020 Accepted: 8 June 2020

Acute liver injury following turmeric use in Tuscany: An analysis of the Italian Phytovigilance database and systematic review of case reports.

Abstract: AIMS Several cases of acute non-infectious cholestatic hepatitis recently appeared in Italy following consumption of Curcuma longa-containing dietary supplements. The aim of this research was to describe the Tuscan (Italy) cases of acute hepatitis and to compare them with similar cases of hepatotoxicity published in the literature by performing a systematic review. METHODS Records of Tuscan cases of acute hepatitis were obtained from the Italian Phytovigilance system. Each spontaneous report was analysed in order to collect all relevant clinical information of patients and information concerning the Curcuma longa-containing dietary supplement. Moreover, both the RUCAM and WHO-UMC systems were used to evaluate the causal relationship between the use of dietary supplement and acute hepatitis. A systematic literature review was performed in MEDLINE and Embase and all case-reports and case-series published in English were included. RESULTS Seven cases of acute hepatitis occurring in Tuscany up to September 2019 are described. In all cases, hepatotoxicity was associated with Curcuma longa formulations with high bioavailability and high dosage of curcumin/curcuminoids. The causal relationship was also supported by the positive dechallenge observed in most cases. In the 23 cases identified through the systematic review, the majority of patients were concomitantly exposed to at least one other medication and 16 of them experienced a positive dechallenge. CONCLUSIONS Within the frame of poorly controlled and regulated products, such as dietary supplements, the evaluation of Italian cases of Curcuma longa-induced acute hepatitis and the systematic review of literature confirmed the association between Curcuma longa and liver injury.

Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19.

Abstract: Hundreds of researchers are working to develop a vaccine and are evaluating drugs to mitigate the adverse health and economic consequences of COVID-19 (Coronavirus disease 19) worldwide. If novel compounds are found, geopolitical and economic variables will determine their introduction to communities. Therefore, finding low-cost and widely accessible drugs for prevention or treatment of COVID-19 would be ideal. A recent study found that ivermectin, an FDA-approved antiparasitic drug, has inhibitory effects on replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ivermectin has broad anti-viral activity through inhibition of viral proteins including importin α/β1 heterodimer and integrase protein. Caly and colleagues reported that the addition of ivermectin at a concentration of 5μM (twice the reported IC50) to Vero-hSLAM cells, 2 h post infection with SARS-CoV-2, resulted in a reduction in the viral RNA load by 99.98% at 48 h. The authors suggested that this drug could reduce the viral load in infected patients, with potential effect on disease progression and spread. While the findings by Caly and colleagues provide some promise, several pharmacokinetic factors limit the immediate translation of their findings, and there is no evidence that the 5μM concentration of ivermectin used by Caly and colleagues in their in vitro SARS-CoV-2 experiment, can be achieved in vivo. First, the pharmacokinetics of ivermectin in humans is well described, and even with the highest reported dose of approximately 1700 μg/kg (i.e., 8.5 times the FDAapproved dose of 200 μg/kg), the maximum plasma concentration was only 0.28μM. Second, 93% of ivermectin is bound to plasma proteins that limit its cellular uptake by endothelial cells. Considering both the total plasma concentration and protein binding, the free plasma concentration of ivermectin would be 250 times lower than the concentration required to reduce viral replication of SARS-CoV-2 in vitro (Figure 1). Third, whilst there is no data on the tissue penetration of ivermectin in human lungs, the total concentration of ivermectin in calves injected with 200 μg/kg reached only 100 ng/g (approx. 0.1μM) in lung tissue, which suggests that its accumulation would not be sufficient to achieve the antiviral effect with conventional doses. Although high doses of ivermectin in adults or children are well tolerated, the clinical effects of ivermectin at a concentration of 5μM range are unknown and may be associated with toxicity. Consequently, ivermectin has in vitro activity against SARS-CoV-2, but this effect is unlikely to be observed in vivo using current dosing. Amidst fear of the pandemic, the public and some physicians are now using ivermectin off-label for prophylaxis or as adjuvant therapy for COVID-19. Because ivermectin is only commercially available as a 3 or 6 mg tablets or a 6 mg/ml oral suspension, in order to administer a high dose, some people may experiment with more concentrated veterinary formulations. These actions are not based on clinical trials and have motivated cautionary statements from institutions such as the FDA against the use of pharmaceutical formulations of ivermectin intended for animals as therapeutics in humans. Potential avenues for further investigation into repurposing ivermectin for SARS-CoV-2 may be to (i) develop an inhaled formulation to efficiently deliver a high local concentration in the lung, whilst minimizing systemic exposure and (ii) evaluate synergistic effects of ivermectin with other compounds that also inhibit SARS-CoV-2 replication. With 18 registered clinical trials (clinicaltrials.gov) evaluating ivermectin for the treatment of COVID-19, this letter highlights the critical need to consider pharmacological principles to guide in vitro and clinical testing when repurposing old drugs for therapeutic use for the SARS-CoV-2 pandemic.

Warfarin dosing algorithms: A systematic review.

Abstract: AIMS Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms. METHODS We systematically searched MEDLINE up to 20 May 2020 and selected studies describing the development, external validation or clinical utility of a multivariable warfarin dosing algorithm. Two investigators conducted data extraction and quality assessment. RESULTS Of 10 035 screened records, 266 articles were included in the review, describing the development of 433 dosing algorithms, 481 external validations and 52 clinical utility assessments. Most developed algorithms were for dose initiation (86%), developed by multiple linear regression (65%) and mostly applicable to Asians (49%) or Whites (43%). The most common demographic/clinical/environmental covariates were age (included in 401 algorithms), concomitant medications (270 algorithms) and weight (229 algorithms) while CYP2C9 (329 algorithms), VKORC1 (319 algorithms) and CYP4F2 (92 algorithms) variants were the most common genetic covariates. Only 26% and 7% algorithms were externally validated and evaluated for clinical utility, respectively, with <2% of algorithm developments and external validations being rated as having a low risk of bias. CONCLUSION Most warfarin dosing algorithms have been developed in Asians and Whites and may not be applicable to under-served populations. Few algorithms have been externally validated, assessed for clinical utility, and/or have a low risk of bias which makes them unreliable for clinical use. Algorithm development and assessment should follow current methodological recommendations to improve reliability and applicability, and under-represented populations should be prioritized.

Strategies to reduce use of antidepressants.

Abstract: Antidepressant prescribing has increased year on year since the introduction of the selective serotonin reuptake inhibitors (SSRIs) in the 1980s. More than 10% of adults in England are now taking antidepressants for depression/anxiety, with a median length of treatment of more than 2 years, but antidepressants can cause side effects and withdrawal symptoms which increase with longer use. Surveys of antidepressant users suggest 30-50% have no evidence-based indication to continue, but coming off antidepressants is often difficult due to fears of relapse, withdrawal symptoms and a lack of psychological treatments to replace maintenance treatment and prevent relapse. GPs should not prescribe antidepressants routinely for mild depressive/anxiety symptoms. Patients starting antidepressants should be advised that they are to be taken for a limited period only, and that there is a risk of withdrawal problems on stopping them. Prescribers should actively review long-term antidepressant use and suggest coming off them slowly to patients who are well. The relationship between SSRI dose and serotonin transporter receptor occupancy suggests that hyperbolic tapering regimes may be helpful for patients with troubling withdrawal symptoms who cannot stop treatment within 4-8 weeks, and tapering strips can allow carefully titrated slower dose reduction over some months. Internet and telephone support to patients wanting to reduce their antidepressants is being trialled in the REDUCE programme. More research is needed to establish the incidence of withdrawal symptoms in representative samples of patients coming off antidepressants, and large randomised controlled trials are needed to test different tapering strategies.

Dosing will be a key success factor in repurposing antivirals for COVID-19.

Abstract: As new treatment modalities are being explored for SARS-CoV-2, efforts to repurpose existing marketed drugs remain an attractive option, as these agents are readily available and have a known safety profile. It is important to recognize that these drugs have not been specifically developed or optimized for the treatment of SARS-CoV-2 infected patients. Success in repurposing efforts will depend on being mindful of first principles around clinical pharmacology and dosing strategies, noting that the dose regimens of existing drugs were developed for different indications. ‘Getting the dose right’ for antivirals being targeted against acute respiratory viruses requires knowledge of potency, pharmacokinetics and viral kinetics to guide rational use. This commentary aims to review those principles of clinical pharmacology that are critical to the successful design and implementation of an optimal dosing regimen for drugs repurposed against SARS-CoV-2, using lopinavir/ritonavir (LPV/r) as an example. We selected LPV/r as it is being considered for the treatment of SARS-CoV-2; however, the standard dosing regimen may not be optimal for this new indication.

Ocrelizumab in relapsing and primary progressive multiple sclerosis: Pharmacokinetic and pharmacodynamic analyses of OPERA I, OPERA II and ORATORIO

Abstract: Aims Ocrelizumab is a humanized monoclonal antibody that selectively targets CD20-positive B cells and is indicated for treatment of patients with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The pharmacokinetics and pharmacodynamics of ocrelizumab in patients with RMS or PPMS patients were assessed. Methods A population pharmacokinetic model was developed based on data from the Phase II study and the Phase III studies OPERA I and OPERA II in patients with RMS. Data from the ORATORIO Phase III study in patients with PPMS became available after model finalization and was used for external model evaluation. Results The ocrelizumab serum concentration vs. time course was accurately described by a two-compartment model with time-dependent clearance. Body weight was found to be the main covariate. The area under the concentration-time curve over the dosing interval was estimated to be 26% higher for patients with RMS weighing 90 kg when compared with the 60-90 kg group. The terminal half-life of ocrelizumab was estimated as 26 days. The extent of B-cell depletion in blood, as the pharmacodynamic marker, was greater with increasing ocrelizumab exposure. Conclusions The pharmacokinetics of ocrelizumab was described with pharmacokinetic parameters typical for an immunoglobulin G1 monoclonal antibody, with body weight as the main covariate. The pharmacokinetics and B-cell depletion in blood were comparable across the RMS and PPMS trials, and the extent of blood B-cell depletion was greater with higher exposure.

Machine learning in pharmacometrics: Opportunities and challenges.

Abstract: The explosive growth in medical devices, imaging and diagnostics, computing, and communication and information technologies in drug development and healthcare has created an ever-expanding data landscape that the pharmacometrics (PMX) research community must now traverse. The tools of machine learning (ML) have emerged as a powerful computational approach in other data-rich disciplines but its effective utilization in the pharmaceutical sciences and PMX modelling is in its infancy. ML-based methods can complement PMX modelling by enabling the information in diverse sources of big data, e.g. population-based public databases and disease-specific clinical registries, to be harnessed because they are capable of efficiently identifying salient variables associated with outcomes and delineating their interdependencies. ML algorithms are computationally efficient, have strong predictive capabilities and can enable learning in the big data setting. ML algorithms can be viewed as providing a computational bridge from big data to complement PMX modelling. This review provides an overview of the strengths and weaknesses of ML approaches vis-a-vis population methods, assesses current research into ML applications in the pharmaceutical sciences and provides perspective for potential opportunities and strategies for the successful integration and utilization of ML in PMX.

Potentially inappropriate prescribing and its associations with health-related and system-related outcomes in hospitalised older adults: A systematic review and meta-analysis.

Abstract: Aims To synthesise associations of potentially inappropriate prescribing (PIP) with health-related and system-related outcomes in inpatient hospital settings. Methods Six electronic databases were searched: Medline Complete, EMBASE, CINAHL, PyscInfo, IPA and Cochrane library. Studies published between 1 January 1991 and 31 January 2021 investigating associations between PIP and health-related and system-related outcomes of older adults in hospital settings, were included. A random effects model was employed using the generic inverse variance method to pool risk estimates. Results Overall, 63 studies were included. Pooled risk estimates did not show a significant association with all-cause mortality (adjusted odds ratio [AOR] 1.10, 95% confidence interval [CI] 0.90-1.36; adjusted hazard ratio 1.02, 83% CI 0.90-1.16), and hospital readmission (AOR 1.11, 95% CI 0.76-1.63; adjusted hazard ratio 1.02, 95% CI 0.89-1.18). PIP was associated with 91%, 60% and 26% increased odds of adverse drug event-related hospital admissions (AOR 1.91, 95% CI 1.21-3.01), functional decline (AOR 1.60, 95% CI 1.28-2.01), and adverse drug reactions and adverse drug events (AOR 1.26, 95% CI 1.11-1.43), respectively. PIP was associated with falls (2/2 studies). The impact of PIP on emergency department visits, length of stay, and health-related quality of life was inconclusive. Economic cost of PIP reported in 3 studies, comprised various cost estimation methods. Conclusions PIP was significantly associated with a range of health-related and system-related outcomes. It is important to optimise older adults' prescriptions to facilitate improved outcomes of care.

Serious adverse events with tocilizumab: Pharmacovigilance as an aid to prioritize monitoring in COVID-19.

Abstract: Given its approval for the treatment of cytokine release syndrome, tocilizumab is under investigation in severe coronavirus disease-2019. To characterize serious adverse events (AEs) with tocilizumab, we queried the worldwide FDA Adverse Event Reporting System and performed disproportionality analysis, selecting only designated medical events (DMEs) where tocilizumab was reported as suspect, with a focus on hepatic reactions. The reporting odds ratios (RORs) were calculated, deemed significant by a lower limit of the 95% confidence interval (LL 95% CI) > 1. A total of 2,433 reports of DMEs were recorded with tocilizumab, mainly in rheumatic diseases. Statistically significant RORs emerged for 13 DMEs, with drug-induced liver injury (n = 91; LL 95% CI 3.07), pancreatitis (151; 1.41), and pulmonary fibrosis (222; 7.21) as unpredictable AEs. A total of 174 cases of liver-related DMEs were retrieved (proportion of deaths = 18.4%), with median onset of 27.5 days. These serious unpredictable reactions occurring in chronic real-world tocilizumab use may support patient care and monitoring of ongoing clinical trials.

Comparison of Infection Risks and Clinical Outcomes in Patients with and without SARS-CoV-2 Lung Infection under Renin-Angiotensin-Aldosterone-System Blockade - Systematic Review and Meta-Analysis

Abstract: AIMS Angiotensin-converting enzyme-2 (ACE2) is the receptor for SARS-CoV-2. Animal studies suggest that renin-angiotensin-aldosterone system (RAAS) blockers might increase the expression of ACE2 and potentially increase the risk of SARS-CoV-2 infection. METHODS AND RESULTS The effect of ACE inhibitor (ACEI) treatment on the pneumonia incidence in non-COVID-19 patients (25 studies, 330 780 patients) was associated with a 26% reduction of pneumonia risk (odds ratio [OR]: 0.74, P < .001). Pneumonia-related death cases in ACEI-treated non-COVID-19 patients were reduced by 27% (OR: 0.73, P = .004). However, angiotensin II receptor blockers (ARB) treatment (10 studies, 275 621 non-COVID-19 patients) did not alter pneumonia risk in patients. Pneumonia-related death cases in ARB-treated non-COVID-19 patients was analysed only in 1 study and was significantly reduced (OR, 0.47; 95% confidence interval, 0.30 to 0.72). Results from 11 studies (8.4 million patients) showed that the risk of getting infected with the SARS-CoV-2 virus was reduced by 13% (OR: 0.87, P = .014) in patients treated with ACEI, whereas analysis from 10 studies (8.4 million patients) treated with ARBs showed no effect (OR, 0.92, P = .354). Results from 34 studies in 67 644 COVID-19 patients showed that RAAS blockade reduces all-cause mortality by 24% (OR = 0.76, P = .04). CONCLUSION ACEIs reduce the risk of getting infected with the SARS-CoV-2 virus. Blocking the RAAS may decrease all-cause mortality in COVID-19 patients. ACEIs also reduce the risk of non-COVID pneumonia. All-cause mortality due to non-COVID pneumonia is reduced by ACEI and potentially by ARBs.

Mass balance, pharmacokinetics and pharmacodynamics of intravenous HSK3486, a novel anaesthetic, administered to healthy subjects.

Abstract: Aims This trial (NCT03751956) investigated the mass balance, pharmacokinetics and pharmacodynamics of HSK3486, a novel anaesthetic, in healthy subjects. Methods A single dose of 0.4 mg/kg [14 C]HSK3486 was administered to six healthy subjects. Blood, urine and faecal samples were collected, analysed for radioactivity, unchanged HSK3486 and profiled for metabolites. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale and vital signs were closely monitored during the study. Results The mean recovery of total radioactivity in excreta was 87.3% in 240 h, including 84.6% in urine and 2.65% in faeces. The exposure (AUC0-t ) of total radioactivity was much higher than that of unchanged HSK3486 in plasma, indicating there were circulating metabolites in plasma. The glucuronide conjugate of HSK3486 (M4) was found as the only major circulating metabolite in plasma (79.3%), while unchanged HSK3486 accounted for only 3.97% of the total radiation exposure. M4 also resulted in a longer estimated elimination half-life (t1/2 ) of total radioactivity than that of unchanged HSK3486 in plasma. Fortunately, the metabolite was detected to be not specific to red blood cells and was suggested to be nonhypnotic and nontoxic. All the subjects were quickly anaesthetized (2 min) after drug administration and woke up smoothly after a short time (5.5-14.1 min) with few residual effects. The only adverse event in the study was mild (grade 1) and consisted of hypotension. Conclusion HSK3486 is a promising anaesthetic candidate with rapid onset of action and clear absorption, distribution, metabolism, excretion (ADME) processes. HSK3486 showed favourable pharmacokinetic characteristics, pharmacodynamic responses and safety at the study dose.

Warfarin and food, herbal or dietary supplement interactions: A systematic review.

Abstract: Aims To present an updated overview on the safety of concurrent use of food, herbal or dietary supplement and warfarin. Methods A systematic literature review was performed on 5 databases from inception up to 31 December 2019. These interactions were classified depending on the likelihood of interaction and supporting evidences. Results A total of 149 articles describing 78 herbs, food or dietary supplements were reported to interact with warfarin. These reports described potentiation with 45 (57.7%) herbs, food or dietary supplements while 23 (29.5%) reported inhibition and 10 (12.8%) reported limited impact on warfarin pharmacokinetics and pharmacodynamics. Twenty unique herb and dietary supplements also reported to result in minor bleeding events, such as purpura and gum bleeding as well as major events such as intracranial bleeding that led to death. Conclusion While most food, herbs and supplements can be safely taken in moderation, healthcare professionals should be aware of the increased risk of bleeding when taking several food and herbs. These include Chinese wolfberry, chamomile tea, cannabis, cranberry, chitosan, green tea, Ginkgo biloba, ginger, spinach, St. John's Wort, sushi and smoking tobacco. Patients should be counselled to continue to seek advice from their healthcare professionals when starting any new herbs, food or supplement.

Cardiovascular adverse events associated with hydroxychloroquine and chloroquine: A comprehensive pharmacovigilance analysis of pre-COVID-19 reports.

Abstract: Aim There is a clinical need for safety data regarding hydroxychloroquine (HCQ) and chloroquine (CQ) during the coronavirus (COVID-19) pandemic. We analysed real-world data using the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) database to assess HCQ/CQ-associated cardiovascular adverse events (CVAEs) in pre-COVID-19 reports. Methods We conducted disproportionality analysis of HCQ/CQ in the FAERS database (07/2014-9/2019), using reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 ). Results The full database contained 6 677 225 reports with a mean (±SD) age of 53 (±17) years and 74% females. We identified 4895 reports of HCQ/CQ related adverse events, of which 696 (14.2%) were CVAEs. Compared with the full database, HCQ/CQ use was associated with a higher reporting rate of major CVAEs, including cardiomyopathy (n = 86 [1.8%], ROR = 29.0 [23.3-35.9]), QT prolongation (n = 43 [0.9%], ROR = 4.5 [3.3-6.1]), cardiac arrhythmias (n = 117 [2.4%], ROR = 2.2 [1.8-2.7]) and heart failure (n = 136 [2.8%], ROR = 2.2 [1.9-2.7], all IC₀₂₅ > 0). No statistically significant differences were observed between sex and age groups. CVAEs were reported more often in patients with systemic lupus erythematosus and Sjogren's syndrome. HCQ/CQ-associated CVAEs demonstrated subsequent hospitalization and mortality rates of 39% and 8%, respectively. Overdose reports demonstrated an increased frequency of QT prolongation and ventricular arrhythmias (35% and 25%, respectively). Conclusion In a real-world setting, HCQ/CQ treatment is associated with higher reporting rates of various CVAEs, particularly cardiomyopathy, QT prolongation, cardiac arrhythmias and heart failure. HCQ/CQ-associated CVAEs result in high rates of severe outcomes and should be carefully considered as an off-label indication, especially for patients with cardiac disorders.

Zinc supplementation as an adjunct therapy for COVID-19: challenges and opportunities.

Abstract: An outbreak of a novel coronavirus (COVID-19 or 2019-CoV) infection has posed significant threats to international health and the economy. Patients with COVID-19 are at risk of cytokine storm, acute respiratory distress syndrome (ARDS), reduced blood oxygenation, mechanical ventilation, and a high death rate. Although recent studies have shown remdesivir and dexamethasone as treatment options, there is an urgent need to find a treatment to inhibit virus replication and to control the progression of the disease. Essential biometal zinc has generated a lot of excitement as one of the promising candidates to reduce the severity of COVID-19 infection. Several published observations outlined in the review are the reasons why there is a global enthusiasm that zinc therapy could be a possible therapeutic option. However, the biggest challenge in realising the therapeutic value of zinc is lack of optimal treatment modalities such as dose, duration of zinc supplementation and the mode of delivery. In this review, we discuss the regulatory mechanism that hinges upon the bioavailability of zinc. Finally, we propose that intravenous zinc could circumvent the confounding factors affecting the bioavailability of zinc and allow zinc to achieve its therapeutic potential. If successful, due to advantages such as lack of toxicity, low cost and ease of availability, intravenous zinc could be rapidly implemented clinically.

A systematic review of economic evaluations of advanced therapy medicinal products

Abstract: Aims Advanced therapy medicinal products (ATMPs) represent a new category of medicinal products with a potential for transformative improvements in health outcomes but at exceptionally high prices. Routine adoption of ATMPs requires robust evidence of their cost-effectiveness. Methods A systematic literature review of economic evaluations of ATMPs, including gene therapies, somatic cell therapies and tissue-engineered products, was conducted. Literature was searched using MedLine, Embase, PubMed, Cochrane Register, the NHS Economic Evaluation Database and the grey literature of health technology assessment organisations with search terms relating to ATMPs and economic evaluations. Titles were screened independently by 2 reviewers. Articles deemed to meet the inclusion criteria were screened independently on abstract, and full texts reviewed. Study findings were appraised critically. Results 4514 articles were identified, of which 23 met the inclusion criteria. There was some evidence supporting the cost-effectiveness of: chimeric antigen receptor T-cell therapy axicabtagene-ciloleucel (Yescarta), embryonic neural stem cells, tumour infiltrating lymphocytes, in vitro expanded myoblast, autologous chondrocyte implantation, ex vivo gene therapy (Strimvelis) and voretigene neparvovec (Luxturna). However, estimates of cost-effectiveness were associated with significant uncertainty and high likelihood of bias, resulting from largely unknown long-term outcomes, a paucity of evidence on health state utilities and extensive modelling assumptions. Conclusion There are critical limitations to the economic evidence for ATMPs, most notably in relation to evidence on the durability of treatment effect, and the reliability of opinion-based assumptions necessary when evidence is absent.

Fatal adverse drug reactions: A worldwide perspective in the World Health Organization pharmacovigilance database

Abstract: Aims Adverse drug reactions (ADRs) are important causes of death. However, the main involved drugs are relatively unknown. The present study was performed to characterise death-related drugs recorded in a large pharmacovigilance database during the last 10 years. Methods A retrospective analysis of VigiBase, the World Health Organization pharmacovigilance database, was performed investigating fatal ADRs registered between 1 January 2010 and 31 December 2019 in male and female patients aged ≥18 years and reported by physicians. Analyses were descriptive investigating age, sex and suspected drugs. Differences in reporting according to sex, age and continents were investigated using disproportionality analysis with calculation of reporting odds ratio and its 95% confidence interval. Results Among the 23 millions ADRs recorded in VigiBase, 3 250 967 were included with 43 685 fatal. They were reported mainly in patients older than 75 years. The 3 most frequently involved drug classes were antineoplastic/immunomodulating drugs followed by nervous system and cardiac drugs. The top 3 individual drugs were denosumab, lenalidomide and thalidomide with marked differences according to age, sex, continents and countries. The risk of reporting fatal ADRs was higher in males, in the Americas and in patients ≥65 years. Conclusion Fatal ADRs registered in a large pharmacovigilance database during the last 10 years correspond to just over 1% of the total number of ADRs. They occurred more in males, after 65 years and with antineoplastic/immunomodulating drugs in general. Our study also highlighted, for the first time, important differences in fatal ADRs between continents and countries.

Clinical outcomes and adverse events in patients hospitalised with COVID-19, treated with off-label hydroxychloroquine and azithromycin.

Abstract: Aims To assess clinical outcomes and adverse drug events in patients hospitalised with COVID-19 treated with off-label hydroxychloroquine (HCQ) and azithromycin (Az). Methods We performed a retrospective analysis of hospitalised patients who had a positive polymerase chain reaction test for SARS-CoV-2 and received HCQ plus Az or no targeted therapy. The primary end point was clinical improvement on day 7 defined as either hospital discharge or an improvement of 2 points on a 6-category ordinal scale. Secondary outcomes included mortality at day 28, intensive care admission, requirement for mechanical ventilation and incidence of adverse events. Results Data from a total of 134 patients were evaluated; 82 patients received HCQ/Az and 52 patients received no targeted therapy. Clinical improvement was seen in 26.8% of patients who received HCQ/Az but this was not significant. The rates of intensive care transfer and mechanical ventilation were higher in the treatment group, but these differences were not significant. Mortality at day 28 was significantly higher in the treatment group (P = .03). Hypoglycaemia elevated liver function tests and QT prolongation were monitored in both groups. The risk of QT prolongation was significantly higher in the treatment group. Treatment was stopped early in 6 (7.3%) patients due to adverse events. Conclusion Although patients who received HCQ/Az were more severely ill the administration of these repurposed drugs did not result in clinical improvement and was associated with a significant increase in toxicity. This descriptive study highlights the importance of monitoring all repurposed agents for adverse events.

Dexamethasone use and mortality in hospitalized patients with coronavirus disease 2019: A multicentre retrospective observational study.

Abstract: AIMS: To examine the association between dexamethasone use and mortality among patients hospitalized for COVID-19. METHODS: We examined the association between dexamethasone use and mortality at AP-HP Greater Paris University hospitals. Study baseline was defined as the date of hospital admission. The primary endpoint was time to death. We compared this endpoint between patients who received dexamethasone and those who did not in time-to-event analyses adjusted for patient characteristics (such as age, sex and comorbidity) and clinical and biological markers of clinical severity of COVID-19, and stratified by the need for respiratory support, i.e. mechanical ventilation or oxygen. The primary analysis was a multivariable Cox regression model. RESULTS: Of 12 217 adult patients hospitalized with a positive COVID-19 reverse transcriptase-polymerase chain reaction test, 171 (1.4%) received dexamethasone orally or by intravenous perfusion during the visit. Among patients who required respiratory support, the end-point occurred in 10/63 (15.9%) patients who received dexamethasone and 298/1129 (26.4%) patients who did not. In this group, there was a significant association between dexamethasone use and reduced mortality in the primary analysis (hazard ratio, 0.46; 95% confidence interval 0.22-0.96, P = .039). Among patients who did not require respiratory support, there was no significant association between dexamethasone use and the endpoint. CONCLUSIONS: In this multicentre observational study, dexamethasone use administered either orally or by intravenous injection at a cumulative dose between 60 mg and 150 mg was associated with reduced mortality among patients with COVID-19 requiring respiratory support.

Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.

Abstract: Aims To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity, physicochemical and pharmacokinetic properties. Methods This escalating-dose, placebo-controlled, cross-over study randomised adults with asthma to 1 or 2 treatment periods with ≥25 days washout in-between. Each treatment period comprised five 7-day dose escalations (μg/d): fluticasone furoate (FF; 25 → 100 → 200 → 400 → 800), fluticasone propionate (FP; 50 → 200 → 500 → 1000 → 2000), budesonide (BUD; 100 → 400 → 800 → 1600 → 3200) or placebo. Airway hyperresponsiveness to adenosine-5'-monophosphate (AMP PC20 ) was assessed on day 8. Plasma cortisol was assessed on day 1 (predose baseline) and from pre-PM dose on day 6 to pre-PM dose day 7 (24-h weighted mean). Results Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC20 dose at which 50% of the maximum effect is achieved [ED50 ] values: 48.52, 1081.27 and 1467.36 μg/d, respectively). Systemic activity (cortisol suppression) ED50 values were 899.99, 1986.05 and 1927.42 μg/d, respectively. The therapeutic index (ED50 cortisol suppression/ED50 AMP PC20 ) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 μg/d and 200 μg/d were both comparable in terms of airway potency with high doses of FP (≥1000 μg twice daily [BID]) and BUD (≥1500 μg/BID). The systemic activity of FF 100 μg/d and 200 μg/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 μg/BID and 250 μg/BID) and BUD (100 μg/BID and 200 μg/BID). Conclusion This study provides evidence that FF can provide more protection against airway hyperresponsiveness, with less systemic activity, than FP or BUD. This suggests that all inhaled corticosteroids are not therapeutically similar and may differ in their therapeutic index. (203162; NCT02991859).

Trends in polypharmacy and potentially inappropriate medication (PIM) in older and middle-aged people treated for diabetes

Abstract: Aims Polypharmacy is common in people with diabetes and is associated with the use of potentially inappropriate medication (PIM). This study aimed to assess trends in the prevalence of polypharmacy and PIM in older and middle-aged people with diabetes. Methods A repeated cross-sectional study using the University Groningen IADB.nl prescription database was conducted. All people aged 45 years and over who were treated for diabetes registered in the period 2012-2016 were included. Polypharmacy was assessed for three age groups. PIMs were assessed using Beers criteria for people ≥65 years old, and PRescribing Optimally in Middle-aged People's Treatments (PROMPT) criteria for 45-64 years old. Chi-square tests and regression analysis were applied. Results The prevalence of polypharmacy increased significantly in all age groups in the study period. In 2016, the prevalence of polypharmacy was 36.9% in patients aged 45-54 years, 50.3% in those aged 55-64 years, and 66.2% in those aged ≥65 years. The prevalence of older people with at least one PIM decreased by 3.1%, while in the middle-aged group this prevalence increased by 0.9% from 2012 to 2016. The most common PIMs in both age groups were the use of long-term high-dose proton pump inhibitors, benzodiazepines and strong opioids without laxatives. Of those, only benzodiazepines showed a decreasing trend. Conclusions Polypharmacy increased in older and middle-aged people with diabetes. While the prevalence of PIM decreased over time in older age, this trend was not observed in middle-aged people with diabetes. Efforts are needed to decrease the use of PIMs in populations already burdened with many drugs, notably at middle age.

The problem of look-alike, sound-alike name errors: Drivers and solutions

Abstract: Look-alike or sound-alike (LASA) medication names may be mistaken for each other, e.g. mercaptamine and mercaptopurine. If an error of this sort is not intercepted, it can reach the patient and may result in harm. LASA errors occur because of shared linguistic properties between names (phonetic or orthographic), and potential for error is compounded by similar packaging, tablet appearance, tablet strength, route of administration or therapeutic indication. Estimates of prevalence range from 0.00003 to 0.0022% of all prescriptions, 7% of near misses, and between 6.2 and 14.7% of all medication error events. Solutions to LASA errors can target people or systems, and include reducing interruptions or distractions during medication administration, typographic tweaks, such as selective capitalization (Tall Man letters) or boldface, barcoding, and computerized physician order entry.

Drug–drug interactions with warfarin: A systematic review and meta-analysis

Abstract: Aims The objective of this paper is to systematically review the literature on drug-drug interactions with warfarin, with a focus on patient-important clinical outcomes. Methods MEDLINE, EMBASE and the International Pharmaceutical Abstract (IPA) databases were searched from January 2004 to August 2019. We included studies describing drug-drug interactions between warfarin and other drugs. Screening and data extraction were conducted independently and in duplicate. We synthesized pooled odds ratios (OR) with 95% confidence intervals (CIs), comparing warfarin plus another medication to warfarin alone. We assessed the risk of bias at the study level and evaluated the overall certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Of 42 013 citations identified, a total of 72 studies reporting on 3 735 775 patients were considered eligible, including 11 randomized clinical trials and 61 observational studies. Increased risk of clinically relevant bleeding when added to warfarin therapy was observed for antiplatelet (AP) regimens (OR = 1.74; 95% CI 1.56-1.94), many antimicrobials (OR = 1.63; 95% CI 1.45-1.83), NSAIDs including COX-2 NSAIDs (OR = 1.83; 95% CI 1.29-2.59), SSRIs (OR = 1.62; 95% CI 1.42-1.85), mirtazapine (OR = 1.75; 95% CI 1.30-2.36), loop diuretics (OR = 1.92; 95% CI 1.29-2.86) among others. We found a protective effect of proton pump inhibitors (PPIs) against warfarin-related gastrointestinal (GI) bleeding (OR = 0.69; 95% CI 0.64-0.73). No significant effect on thromboembolic events or mortality of any drug group used with warfarin was found, including single or dual AP regimens. Conclusions This review found low to moderate certainty evidence supporting the interaction between warfarin and a small group of medications, which result in increased bleeding risk. PPIs are associated with reduced hospitalization for upper GI bleeding for patients taking warfarin. Further studies are required to better understand drug-drug interactions leading to thromboembolic outcomes or death.

Changes in antibiotic prescribing following COVID-19 restrictions: Lessons for post-pandemic antibiotic stewardship.

Abstract: Aims Public health responses to reduce SARS-CoV-2 transmission have profoundly affected the epidemiology and management of other infections. We examined the impact of COVID-19 restrictions on antibiotic dispensing in Australia. Methods We used national claims data to investigate antibiotic dispensing trends from November 2015 to October 2020 and whether changes reflected reductions in primary care consultations. We used interrupted time series analysis to quantify changes in monthly antibiotic dispensing and face-to-face and telehealth GP consultations and examined changes by recipient age, pharmacy State and prescriber specialty. Results Over the study period, an estimated 19 921 370 people had 125 495 137 antibiotic dispensings, 71% prescribed by GPs. Following COVID-19 restrictions, we observed a sustained 36% (95% CI: 33-40%) reduction in antibiotic dispensings from April 2020. Antibiotics recommended for managing respiratory tract infections showed large reductions (range 51-69%), whereas those recommended for non-respiratory infections were unchanged. Dispensings prescribed by GPs decreased from 63.5 per 1000 population for April-October 2019 to 37.0 per 1000 for April-October 2020. Total GP consultation rates remained stable, but from April 2020, 31% of consultations were telehealth. Conclusion In a setting with a low COVID-19 incidence, restrictions were associated with a substantial reduction in community dispensings of antibiotics primarily used to treat respiratory infections, coincident with reported reductions in respiratory viral infections. Our findings are informative for post-pandemic antimicrobial stewardship and highlight the potential to reduce inappropriate prescribing by GPs and specialists for respiratory viral infections.

Population pharmacokinetic and optimization of polymyxin B dosing in adult patients with various renal functions.

Abstract: Aims Current FDA-approved label recommends that the dosage of polymyxin B should be adjusted according to renal function. However, the correlation between polymyxin B pharmacokinetics (PK) and creatinine clearance (CrCL) is poor. This study aimed to develop a population PK model of polymyxin B in adult patients with various renal functions and to identify a dosing strategy. Methods A retrospective PK study was performed in 32 adult patients with various renal function. Nonlinear mixed effects modelling was applied to build a population PK model of polymyxin B followed by Monte Carlo simulations which designed polymyxin B dosing regimens across various renal function. Results Polymyxin B PK analyses included 112 polymyxin B concentrations at steady state from 32 adult patients, in which 71.9% of them were critically ill. In the final PK model, CrCL was the significant covariate on CL (typical value 1.59 L/h; between-subject variability 13%). The mean (SD) individual empirical Bayesian estimate of CL was 1.75 (0.43) L/h. In addition, a new dosing strategy combining the PK/pharmacodynamic (PD) targets and Monte Carlo simulation indicated that the reduction of polymyxin B dose in patients with renal insufficiency improved the probability of achieving optimal exposure. For severe infections caused by organisms with minimum inhibitory concentration (MIC) ≥ 2 mg/L, a high daily dose of polymyxin B might be possible for bacterial eradication, but the risk of nephrotoxicity is increased. Conclusions Renal function plays a significant role in polymyxin B PK, and the dose of polymyxin B should be adjusted according to CrCL in patients with renal insufficiency.

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator.

Abstract: Aims A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers. Methods In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed. Results LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. Cmax , AUC0-24 and AUC0-inf increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected. Conclusions These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.

Impact of the Goal-directed Medication Review Electronic Decision Support System on Drug Burden Index: A cluster-randomised clinical trial in primary care.

Abstract: AIMS The Goal-directed Medication Review Electronic Decision Support System (G-MEDSS) assesses and reports a patient's goals, attitudes to deprescribing and Drug Burden Index (DBI) score, a measure of cumulative exposure to anticholinergic and sedative medications. This study evaluated the effect of implementing G-MEDSS in home medicines reviews (HMRs) on DBI exposure and clinical outcomes. METHODS A cluster-randomised clinical trial was performed across Australia. Accredited clinical pharmacists were randomised into intervention (G-MEDSS with usual care HMR) or comparison groups (usual care HMR alone). Patients were recruited by pharmacists from those routinely referred by general practitioners for HMR. The primary outcome was the proportion of patients with any reduction in DBI at 3-months follow-up. Secondary outcomes included change in DBI continuous score at 3-months, HMR recommendations to change DBI and clinical outcomes. RESULTS There were 201 patient participants at baseline (n = 88 intervention, n = 113 comparison), with 159 followed-up at 3-months (n = 63 intervention, n = 96 comparison). The proportion of patients with a reduction in DBI was not significantly different at 3-months (intervention 17%, comparison 11%; adjusted odds ratio 1.44, 95% confidence interval 0.56-3.80). Regarding secondary outcomes, there was no difference in change in DBI score at 3-months. However, the HMR report made recommendations to reduce DBI for a significantly greater proportion of patients in the intervention than in the comparison group (intervention 37%, comparison 14%; adjusted odds ratio 3.20, 95% confidence interval 1.50-6.90). No changes were observed in clinical outcomes. CONCLUSION Implementation of G-MEDSS within HMR did not reduce patients' DBI at 3 months compared with usual care HMR.