Abstract Aim: To compare the effectiveness and safety of two high-intensity atorvastatin doses (40mg vs. 80mg) among acute coronary syndrome (ACS) patients. Methods: This retrospective observational cohort study using real-world data included patients admitted with ACS to the Heart Hospital in Qatar between January 1, 2017 and December 31, 2018. The primary endpoint was a composite of cardiovascular disease (CVD)-associated death, non-fatal ACS, and non-fatal stroke. Cox proportional hazard regression analysis was used to determine the association between the two high-intensity atorvastatin dosing regimens and the primary outcome at 1 month and 12 months post-discharge. Results: Of the 626 patients included in the analyses, 475 (75.9%) received atorvastatin 40mg, while 151 (24.1%) received atorvastatin 80mg following ACS. Most of the patients were Asian (73%), male (97%) with a mean age of 50 years, and presented with ST-elevation myocardial infarction (60%). The incidence of the primary effectiveness outcome did not differ between the atorvastatin 40mg and 80mg groups at 1 month (0.8% vs. 1.3%; aHR= 0.59, 95% CI 0.04-8.13, p= 0.690) and at 12 months (3.2% vs. 4%; aHR= 0.57, 95% CI 0.18-1.80, p= 0.340). Similarly, the use of the two doses of atorvastatin resulted in comparable safety outcomes, including liver toxicity, myopathy, and rhabdomyolysis with an event rate of < 1% in both groups. Conclusion: The use of atorvastatin 40mg in comparison to atorvastatin 80mg in patients with ACS resulted in similar cardiovascular effectiveness and safety outcomes.

Aims: This study investigated the safety, tolerability, and PK after administration of a specific Cannabis sativa cultivar extract, standardised to CBD content as sublingual wafer or oil formulation compared to nabiximols oromucosal spray. Methods: For the single-dose study, the design was an open-label, four-way crossover in 12 healthy volunteers randomised to receive a sequence of four different single doses of CBD as a sublingual wafer (25 or 50 mg CBD), oil solution (50 mg CBD), or nabiximols oromucosal spray (20 mg CBD, 21.6 mg THC). For the multiple-dose study, sublingual wafer (50 mg CBD) was administered twice a day for five days. Results: The extract was generally well tolerated by participants when administered in either wafer or oil form, with some adverse events, including mild or moderate somnolence, sedation and altered mood. The relative bioavailability of CBD after administration as a sublingual wafer was comparable with that of oil solution with 90% confidence interval of 83–131%. The median maximum concentrations of CBD after administration of oil solution and wafer was 9.4 and 11.9 ng mL-1, respectively. Maximum concentrations of CBD occurred 4 hours after administration, with an estimated terminal elimination half-life of 6 hours. There was no statistically significant difference between the AUC0-t of CBD after administration of oil solution or wafer compared with nabiximols oromucosal spray. Conclusion: Oil solution and sublingual wafer formulations of the extract standardised with CBD were well tolerated and demonstrated safe and achieved equivalent concentrations of CBD when compared to an available commercial formulation.

A document by Joga Gobburu. Click on the document to view its contents.

Aim: Asian patients are known to be more prone to bleeding complications than patients of other ethnicities. Therefore, there are possibilities of other risk factors that should be given special consideration for dosage adjustment in this specific ethnic group. This study aimed to investigate the risk factors for bleeding complications in Asian patients under appropriate edoxaban dosage regimens. Methods: Data on patients taking proper dosages, based on the Lixiana package insert, were analyzed. Univariate and multivariable analyses were conducted to evaluate associations between risk factors and bleeding outcomes. Subgroup analysis was performed on high-risk patients for bleeding complications whose edoxaban dose was reduced according to the package insert. Results: A total of 346 patients were included. Among them, 32 patients experienced bleeding complications. Patients with either weights of less than or equal to 60 kg and with cancer showed around 3.3- and 3.4-fold increased risk of bleeding complications compared to heavier patients ( > 60 kg) and those without cancer, respectively. In subgroup analysis with high-risk patients who took low-dose edoxaban (15 mg and 30 mg), weights of less than or equal to 60 kg remained a significant factor for bleeding outcomes. Conclusion: This study showed that weights of less than or equal to 60 kg and the presence of cancers could affect bleeding complications which occurred despite proper edoxaban treatment in Asian patients. Therefore, more strict dosage guideline could be considered in populations with high proportions of Asian ethnicities.

In the context of the current COVID-19 pandemic, what are the lessons clinical pharmacology could learn to improve our teaching practice and involvement in research and ethics committees to make sure we are better prepared for the next emergency. Is there something in the light of the hydroxychloroquine hype that we as clinical pharmacologists or our professional societies could have done better? We propose updating the way we teach about drug development, rules and ethics of off-label prescribing and critical appraisal of primary sources when guidelines and top-level evidence are not available. Clinical pharmacology should play a leading role in the future re-definition of processes and guidelines for emergencies such as the one we faced in 2020.

Dear editor,Given time, drug discovery programmes will undoubtedly yield highly potent drugs to form the basis of optimised COVID-19 regimens. However, if efficacious therapies can be identified from current medicines, repurposing represents the fastest route to establish deployable interventions and buy time for vaccine and novel drug development. It is important to note that effective medicines were rigorously optimised for the treatment of specific indications. Route of administration, dosage and schedules for existing therapies were optimised to provide adequate plasma/tissue pharmacokinetics and safety for their target disease or condition. These cannot be assumed to be optimal for COVID-19 but are often highly predictable from pre-existing data and clinical experience. For example, hydroxychloroquine and lopinavir/ritonavir recently failed to deliver benefits in RCTs for mild/moderate and severe disease,1, 2 but the clear disconnect between reportedin vitro antiviral activity and known human pharmacokinetics after administration of approved doses was predictable.3Interpretation of laboratory-based antiviral activity assessments is complicated by current uncertainty regarding the appropriateness of the existing model systems. The majority of in vitro antiviral screening assays have utilised Vero cells, which were derived from the kidney of African Green Monkey in the 1970s, and the lack of clinical evidence for which to validate the exposure-response relationship in humans is problematic. Evidence is emerging that the anti-SARS-CoV-2 activity of drugs may be higher in cells derived from humans. However, the question of which cell types are most representative of in vivo performance is yet to be addressed, and all that can really be concluded from current knowledge is that the susceptibility of SARS-CoV-2 to antivirals is cell-type-dependent. The consequences of this in terms of the variety of cell types known to be infected and/or sustain productive infection in vivo is equally uncertain, and further exacerbated by the lack of robustly validated animal models. However, repurposed drugs cannot be assumed to be active against SARS-CoV-2 at a dose that was optimised on the basis of potency for and accumulation at their initial therapeutic target.Nucleoside/nucleotide polymerase inhibitors have proven highly successful for other viruses, but usually require combination with another drug class. Remdesivir and favipiravir have in vitro anti-SARS-CoV-2 activity across multiple studies, and the unprecedented speed at which they have transitioned through COVID-19 RCTs can only be commended.4, 5, 6 Daily IV infusion may make inherent sense for severely ill patients, but a transformational impact for COVID-19 can only be realised if wide compatibility with global healthcare systems and equitable access across all country contexts is achieved. While reduction in symptom duration may mitigate healthcare saturation in high-income countries, the absence of a clear benefit for mortality diminishes game-changing potential. However, the clinical validation of the antiviral activity of such drugs will make them clear candidates for implementation as part of community-based interventions if other challenges are addressed. Importantly, the combination of nucleoside analogues with a secondary target such as the protease has stood the test of time in antiviral pharmacology. The recent reports of low-dose dexamethasone leading to an impact on mortality7 is a significant step forward but long-term mitigation of viral transmission, with subsequent economic and social restrictions, requires antiviral treatment or prevention to minimise hospitalisation through a community-targeted approach.Focussing on existing single drugs, and not appropriately formulated medicines, will require the rethinking of a number of medicine development parameters such as posology, reformulation and therapeutic index (Figure 1); current HIV medicines, for example, are formulated for chronic (life-long) dosing to moderate and control disease but a successful COVID-19 therapy will likely require only a short term acute administration to rapidly cure the patient. Conversely, different considerations are required for longer-term applications in COVID-19 chemoprophylaxis, which could have a dramatic effect on control of the pandemic.Many advanced drug delivery technologies have emerged in recent years. Long-acting drug delivery involving injectable, implantable or microarray patch mediated delivery have attracted enormous recent interest for prevention of other infectious diseases,8, 9 and the ability to deliver potent antiviral combinations for a period of months could play a transformational role in the absence of a safe and efficacious vaccine. The physicochemistry and activity of the polymerase inhibitors, and other drugs with known anti SARS-Cov-2 activity, also warrants investigation of pulmonary delivery via nebuliser or metered dose inhaler for direct dosing to the upper airways to supplement systemic drug delivery as pre- or post-exposure prophylaxis. Several advanced drug delivery strategies can be applied rapidly and do not need to be prohibitively expensive for global community programmes. It seems unlikely that a global pandemic can be ended if effective medicines are only available to the few and equitable access is therefore of benefit to all. Importantly, relying solely upon pre-existing formulations and posologies optimised for other diseases carries inherent risk of rejecting drug candidates with an otherwise high potential for global impact.

Abstract Prescription medicine misuse, especially misuse of opioids has become a major public healthcare issue in many developed countries such as the United States of America and Australia where this is associated with significant morbidity (Emergency Department visits due to acute toxicity) and mortality. In this review, we looked at the available data obtained from peer-reviewed articles and population surveys to gain an insight into the current situation in the Asia Pacific region. There is currently limited information available, but data from subpopulation surveys in a number of countries suggests that prescription medicine misuse is likely to be an issue of concern from a public health perspective in the Asia Pacific region. The available data suggest that misuse prevalence rates and the medicines that are commonly misused are similar to countries such as the USA and United Kingdom. Further studies are required to determine the overall prevalence of misuse, the harms associated with this and the sources of drugs being misused so that appropriate interventions can be implemented to tackle issues related to prescription medicine misuse in this region. Keywords: Prescription medicine misuse, drug abuse, opioids, benzodiazepines, GABA analogues

Clinicians, patients, administrators and researchers have become increasingly frustrated by the lack of indication (i.e. problem) information included in prescriptions, despite the obvious benefit this would provide to patients and other healthcare providers [1]. Medication indications are not routinely documented by prescribers, both in inpatient and outpatient settings.[2, 3] Calls have been made to introduce a sixth ‘right’ into the medication management process, whereby the right patient is given the right drug and dose at the right time via the right route for the right indication [4]. Indications-based prescribing has recently gained traction as a potential way forward to facilitate indication documentation [4, 5]. Indications-based prescribing, not currently supported by most electronic prescribing systems (EPSs), describes the scenario where prescribers initially select an indication, not a medication, and the EPS presents the user with suggested medications for addressing the problem. There are clear advantages with this approach, including those associated with guided prescribing (e.g. more appropriate drug selections) and with indication documentation (e.g. improved communication between providers), prompting work to begin on developing EPS functionality in the US to support indications-based prescribing. In a recent usability evaluation of a prototype of this functionality, indications-based prescribing was more efficient to use, resulted in fewer medication errors and in higher usability scores than the traditional EPS functionality [6].

Gene therapy medicinal products have the potential to provide curative treatment to many diseases with current limited therapeutic options. As advanced therapy medicinal products (ATMPs), these therapies undergo a centralised, single European Union authorisation by the European Medicines Agency, but the risks, and potential harm to the environment and population at large are weighted in each application, and different interpretations at national level exist. A streamlined procedure is now in place to facilitate a consistent approach for the assessment of the environmental risks of medicines containing genetically modified organisms. This article provides an overview of basic requirements across the EU, an overview of the new streamlined process and discusses available guidance for developers. All these initiatives are aimed to remove hurdles for ATMP developers and facilitate faster access to patients.

Background and Purpose: SARS-coV-2 pandemic continues to cause an unprecedented global destabilization. There is an urgent need to develop vaccines or identify molecules to treat severe cases and repurposing of drugs is the best approach at this hour. Thalidomide, despite having an infamous history has been successfully repurposed and tested for various disease conditions including inflammatory diseases and tumor. Few reports emphasize the use of thalidomide with a SARS-coV-2 pneumonia patient being successfully treated with thalidomide. Experimental Approach: A meta-analysis comparing the transcriptomes of SARS-coV-2 infected tissues with thalidomide and lenalidomide-induced transcriptomic changes in transformed lung, endothelial and hematopoietic models was performed. Key Results: Thalidomide and lenalidomide exhibited pleiotropic effects affecting a range of biological processes including inflammation, immune response, angiogenesis, MAPK signaling, NOD-like receptor signaling, TLR signaling, leukocyte differentiation and innate immunity, the processes which are aberrantly regulated in severe COVID-19 patients. In addition, we show the similarities between the expression profiles of SARS-coV-2 infected lung and systemic lupus erythematous. Conclusion and Implications: The present study recommends thalidomide analogs as a “better fit” to treat severe cases of novel viral infections, healing the damaged network by compensating the impairment caused by the Coronavirus disease-2019 (COVID-19).

Aim: We hypothesize that the efficacy of COVID-19 therapeutic candidates will be better predicted by understanding their effects at various points on a viral cell cycle, in particular, the specific rate constants, and that drugs acting independently of these specific discrete sites may not yield expected efficacy. We hypothesize that drugs, or combinations of drugs that act at specific multiple sites on the viral life cycle have the highest probability of success in the treatment of early infection phase in COVID-19 patients. Methods: Using a target cell limited model structure that had been used to characterize viral load dynamics from COVID-19 patients, we performed simulations to show that combinations of therapeutics targeting specific rate constants have greater probability of efficacy and supportive rationale for clinical trial evaluation. Results: Based on the known kinetics of the SARS-CoV-2 life cycle, we rank ordered potential targeted approaches involving repurposed, low-potency agents. We suggest that targeting multiple points central to viral replication within infected host cells or release from those cells is a viable strategy for reducing both viral load and host cell infection. In addition, we observed that the time-window opportunity for a therapeutic intervention to effect duration of viral shedding exceeds the effect on sparing epithelial cells from infection or impact on viral load AUC. Furthermore, the impact on reduction on duration of shedding may extend further in patients who exhibit a prolonged shedder phenotype. Conclusions: Our work highlights the use of model-informed tools to better rationalize effective treatments for COVID-19.

Aim: Although medicine misuse is a public health issue, it has multiple meanings in the medical literature. This study aimed to characterize, classify and identify the most appropriate definitions of medicine misuse. Methods: A systematic review was performed in Medline, ISI Web of Science, SocINDEX, PsycInfo, PsycArticles, and Psychological and Behavioral Sciences Collection, using keywords related to misuse, appropriateness, and medicine between November 1st, 2008 and November 1st, 2018. Additional searches were conducted in websites of regulatory agencies and public health institutions. Two authors independently selected studies providing both definitions and examples of misuse, while a third resolved disagreements. Definitions were used to propose a hierarchical classification based on initiator, intent, purpose, and context of medicine misuse. The study is registered on PROSPERO: CRD42018115789. Results: Of 2,901 identified records, 44 were included. A total of 63 definitions and 60 examples of misuse were retrieved. When the prescriber is initiator and according to intent, potential medicine misuse referred to “intentional or unintentional prescribing not in line with clinical evidence”. Based on context, he could prescribe medicines not clinically justified, i.e. “overprescribing”, or prescribe indicated medicines incorrectly, i.e. “misprescribing”. Among other groups of definitions, those overlapping with drug abuse or medication use errors were considered out-of-scope. Conclusion: This systematic review provides a comprehensive overview of the terms and definitions used to characterize medicine misuse and could serve as a basis for a terminology that makes clear distinctions between misuse, abuse, and errors.

Background Medication harm has negative clinical and economic consequences, contributing to hospitalisation, morbidity and mortality. The incidence ranges from four to 14%, of which up to 50% of events may be preventable. A predictive model for identifying high-risk inpatients can guide a timely and systematic approach to prioritisation. Aim To develop and internally validate a risk prediction model, for prioritisation of hospitalised patients, at risk of medication harm. Methods A retrospective cohort study was conducted in general medical and geriatric specialties at an Australian hospital, over six months. Medication harm was identified using International Classification of Disease (ICD-10) codes and the hospital’s incident database. Sixty-eight variables, including medications and laboratory results, were extracted from the hospital’s databases. Multivariable logistic regression was used to develop the final risk model. Performance was evaluated using area under the receiver operative characteristic curve (AuROC) and clinical utility was determined using decision curve analysis. Results The study cohort included 1982 patients median age 74 years, of which 136 (7%) experienced ≥1 adverse medication event(s). The model included: length of stay, hospital re-admission within 12 months, venous or arterial thrombosis &/or embolism, ≥ 8 medications, serum sodium < 126 mmol/L, INR > 3, anti-psychotic, antiarrhythmic and immunosuppressant medications, and history of medication allergy. Validation gave an AuROC of 0.70 (95% CI: 0.65-0.74). Decision curve analysis identified that the AIME may be clinically useful to help guide decision making in practice. Conclusion We have developed a risk prediction model with reasonable performance. Future steps include external validation.

Background Medication harm has negative clinical and economic consequences, contributing to hospitalisation, morbidity and mortality. The incidence ranges from four to 14%, of which up to 50% of events may be preventable. A predictive model for identifying high-risk inpatients can guide a timely and systematic approach to prioritisation. Aim To develop and internally validate a risk prediction model, for prioritisation of hospitalised patients, at risk of medication harm. Methods A retrospective cohort study was conducted in general medical and geriatric specialties at an Australian hospital, over six months. Medication harm was identified using International Classification of Disease (ICD-10) codes and the hospital’s incident database. Sixty-eight variables, including medications and laboratory results, were extracted from the hospital’s databases. Multivariable logistic regression was used to develop the final risk model. Performance was evaluated using area under the receiver operative characteristic curve (AuROC) and clinical utility was determined using decision curve analysis. Results The study cohort included 1982 patients median age 74 years, of which 136 (7%) experienced ≥1 adverse medication event(s). The model included: length of stay, hospital re-admission within 12 months, venous or arterial thrombosis &/or embolism, ≥ 8 medications, serum sodium < 126 mmol/L, INR > 3, anti-psychotic, antiarrhythmic and immunosuppressant medications, and history of medication allergy. Validation gave an AuROC of 0.70 (95% CI: 0.65-0.74). Decision curve analysis identified that the AIME may be clinically useful to help guide decision making in practice. Conclusion We have developed a risk prediction model with reasonable performance. Future steps include external validation.

Problematic polypharmacy is a growing challenge. Medication that is intended to improve patients’ health and wellbeing is instead becoming part of the problem. The way we practice medicine has become one of the drivers for the problems. Dealing with the challenge will need us to think differently about how we do clinical care. A 2013 Kings Fund report stated that tackling problematic polypharmacy requires us to actively build a principle of ‘compromise’ in to the way we use medicines. There are implications for how we consult and make decisions with patients, in how we design health practice and systems to support that decision making, and in our understanding of the process of research – how we generate the knowledge that informs practice. This review considers the current state of play in all three areas and identifies some of the work still need to do in order to generate the practice-based evidence needed to tackle this most challenging problem. Finding a way to redesign practice to address problematic polypharmacy could offer a template for tackling other related complex issues facing medical practice such as multimorbidity, chronic pain and complex mental health.

Mitotane is the only drug approved for treating adrenocortical carcinoma (ACC) by the FDA since 1959, despite the controversy regarding its efficacy in prolonging patient survival. This drug has cytotoxic effects on tumor tissue by inducing cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids involved in the pathogenesis of ACC. To reach the therapeutic plasma concentration, high doses of mitotane are usually necessary, which may result in several adverse effects. This suggests that important pharmacological features are involved in the mechanisms of action of this drug, such as first pass metabolism, tissue accumulation, and extensive time needed for drug elimination. However, few studies have reported the pharmacological aspects of mitotane, and they did not provide sufficient evidence regarding monitoring mitotane’s therapeutic effects. Therefore, this review summarized the chemistry, pharmacokinetics and pharmacodynamics, therapeutic effects, toxic effects, and new perspectives of mitotane treatment that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can further provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

Aims The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the non-clinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by species-specificity. The elements of the non-clinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013-2018 to identify the approach followed for non-clinical development of these products. Methods The purpose of the in vivo studies was designated to be (a combination of) pharmacology/proof-of-concept, safety, biodistribution and/or tumourigenicity. For biodistribution and tumourigenicity also the need for, type and design of in vitro and in vivo studies were recorded. Results In vivo studies for cell-based therapies were primarily aimed at proof-of-concept (75/86), followed by addressing safety (64/86), biodistribution (49/86) or tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for six (out of 86) products, which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. In vivo tumourigenicity studies were regarded of limited value. Conclusions Compared to more conventional medicinal products, the non-clinical development program for cell-based products was more tailored and focussing on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.

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 nitazoxanide 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 nitazoxanide 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.