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Improved global access to novel age‐appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age‐appropriate paediatric medicines. This position paper recommends the use of a paediatric Quality Target Product Profile as an efficient tool to facilitate early planning and decision making across all teams involved in paediatric formulation development during the children‐centric formulation design for new chemical entities, or to repurpose/reformulate off‐patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age‐appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure postmarketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however, the proposed paediatric Quality Target Product Profile could be a valuable collaborative tool for planning and decision making to expedite paediatric product development, particularly for those with limited experience in developing a paediatric product. [ABSTRACT FROM AUTHOR]

A recent article in the British Journal of Clinical Pharmacology discusses a method developed by Saito et al. to measure the concentrations of biologic agents in dried milk spots. The study provides insights into the pharmacokinetic properties of these agents and offers clinically important information for their safe use. However, the authors suggest that additional data on analyte stability in the filter paper and the integrity of the analytes extracted from breast milk are needed. They also question the conclusions drawn from the study and recommend further evaluation of the effects of variability in dried spots and the need for separate analysis for each drug. Overall, more validation and evaluation are required before applying this method in clinical trials or practice. [Extracted from the article]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Electronic prescribing reduces drug prescription errors and therefore improves patient safety. • Whether electronic prescribing compared with prescribing on paper facilitates the implementation of clinical pharmacologists' recommendations in the care of patients hospitalized with medical problems is not known. WHAT THIS STUDY ADDS • The use of electronic prescriptions when compared with handwritten prescriptions increased the uptake of clinical pharmacologists' recommendations for improving drug safety in hospitalized patients. AIMS To determine whether electronic prescribing facilitates the uptake of clinical pharmacologists' recommendations for improving drug safety in medical inpatients. METHODS Electronic case records and prescription charts (either electronic or paper) of 502 patients hospitalized on medical wards in a large Swiss teaching hospital between January 2009 and January 2010 were studied by four junior and four senior clinical pharmacologists. Drug-related problems were identified and interventions proposed. The implementation and time delays of these proposed interventions were compared between the patients for whom paper drug charts were used and the patients for whom electronic drug charts were used. RESULTS One hundred and fifty-eight drug-related problems in 109 hospital admissions were identified and 145 recommendations were made, of which 51% were implemented. Admissions with an electronic prescription chart ( n= 90) were found to have 2.74 times higher odds for implementation of the change than those with a paper prescription chart ( n= 53) (95% confidence interval 1.2, 6.3, P= 0.018, adjusted for any dependency introduced by patient, ward or clinical team; follow-up for two cases missing). The time delay between recommendations being made and their implementation (if any) was minimal (median 1 day) and did not differ between the two groups. CONCLUSIONS Electronic prescribing in this hospital setting was associated with increased implementation of clinical pharmacologists' recommendations for improving drug safety when compared with handwritten prescribing on paper. [ABSTRACT FROM AUTHOR]

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Figures from the editors selected issue highlights that will be displayed each month in the journal image carousel on the BJCP homepage http://bpspubs.onlinelibrary.wiley.com/hub/journal/10.1111/(ISSN)1365-2125/ Serge Cremers Children are the future. Diep and colleagues from Ionis Pharmaceuticals describe a PK/PD model for their company's antisense oligonucleotide (ASO) drug in development for transthyretin amyloidosis. Let us hope we get some results before it is too late. https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15509 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15511 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.15539 Finally, we had almost forget about our usual clinical pharmacology papers which span from drug safety epidemiology and prescription papers to pharmacogenetics, PK/PD modelling, experimental medicine and translational phase 1 papers. [Extracted from the article]

Upscaling of medication adherence interventions to routine care is still challenging. This realist theory‐inspired review aimed to assess which intervention aspects are potentially important for the scalability of effective cardiovascular disease (CVD) medication adherence interventions and how they are reported in effectiveness studies. A total of 4097 articles from four databases were screened of which ultimately 31 studies were included. Relevant information on scalability was extracted using a theoretic framework based on the scalability assessment tool used in the QUALIDEC study for the following domains: (i) innovation, (ii) implementers and patients, (iii) adopting organizations and health system, and (iv) socio‐political context. Extracted articles were analysed for themes and chains of inference, which were grouped based on commonality and source of evidence to form new hypotheses. Six different domains relevant for scalability of adherence interventions were identified: (1) Complexity of the intervention; (2) training; (3) customization of the intervention; (4) drivers of the intervention; (5) technical interventions; and (6) stakeholder involvement. These six domains might be useful for the development of more scalable interventions by bridging the gap between research and practice. Data relevant for scalability is not well reported on in effectiveness trials for CVD medication adherence interventions and only limited data on scalability has been published in additional papers. We believe the adoption and reach of effective CVD medication adherence interventions will improve with increased awareness for the necessity of scalability in all phases of intervention development. [ABSTRACT FROM AUTHOR]

Aims: The prevalence of dementia is rising as life expectancy increases globally. Behavioural and psychological symptoms of dementia (BPSD), including agitation and aggression, are common, presenting a challenge to clinicians and caregivers. Methods: Following PRISMA guidelines, we systematically reviewed evidence for gabapentin and pregabalin against BPSD symptoms of agitation or aggression in any dementia, using six databases (Pubmed, CINHL, PsychINFO, HealthStar, Embase, and Web of Science). Complementing this formal systematic review, an illustrative case of a patient with BPSD in mixed Alzheimer's/vascular dementia, who appeared to derive benefits in terms of symptom control and functioning from the introduction of gabapentin titrated up to 3600 mg day−1 alongside other interventions, is presented. Results: Twenty‐four relevant articles were identified in the systematic review. There were no randomized trials. Fifteen papers were original case series/case reports of patients treated with these compounds, encompassing 87 patients given gabapentin and six given pregabalin. In 12 of 15 papers, drug treatment was effective in the majority of cases. The remaining nine papers were solely reviews, of which two were described as systematic but predated PRISMA guidelines. Preliminary low‐grade evidence based on case series and case reviews suggests possible benefit of gabapentin and pregabalin in patients with BPSD in Alzheimer's disease. These benefits cannot be confirmed until well‐powered randomized controlled trials are undertaken. Evidence in frontotemporal dementia is lacking. Conclusion: Gabapentin and pregabalin could be considered for BPSD when medications having stronger evidence bases (risperidone, other antipsychotics, carbamazepine and citalopram) have been ineffective or present unacceptable risks of adverse outcomes. [ABSTRACT FROM AUTHOR]

This paper aims to explore the possibility of employing large language models (LLMs) – a type of artificial intelligence (AI) – in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual‐use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual‐use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks. [ABSTRACT FROM AUTHOR]

The British Journal of Clinical Pharmacology highlights several papers in its latest issue. One paper discusses the updated EMA guideline on medicinal products containing genetically modified cells. Two other papers focus on adherence, with one reporting that research underestimates non-adherence and the other suggesting that patient-reported daily doses can improve estimates of adherence. The issue also includes a study on the use of artificial intelligence in pharmacovigilance and a report on high-fidelity simulation medical education training in acute clinical toxicology. Lastly, a study from South Africa examines determinants of early changes in serum creatinine in individuals starting antiretroviral therapy for HIV. [Extracted from the article]

Quantitative systems pharmacology (QSP) is a relatively new discipline within modelling and simulation that has gained wide attention over the past few years. The application of QSP models spans drug‐target identification and validation, through all drug development phases as well as clinical applications. Due to their detailed mechanistic nature, QSP models are capable of extrapolating knowledge to predict outcomes in scenarios that have not been tested experimentally, making them an important resource in experimental and clinical pharmacology. However, these models are complicated to work with due to their size and inherent complexity. This makes many applications of QSP models for simulation, parameter estimation and trial design computationally intractable. A number of techniques have been developed to simplify QSP models into smaller models that are more amenable to further analyses while retaining their accurate predictive capabilities. Different simplification techniques have different strengths and weaknesses and hence different utilities. Understanding the utilities of different methods is essential for selection of the best method for a particular situation. In this paper, we have created an overall framework for model simplification techniques that allows a natural categorisation of methods based on their utility. We provide a brief description of the concept underpinning the different methods and example applications. A summary of the utilities of methods is intended to provide a guide to modellers in their model endeavours to simplify these complicated models. [ABSTRACT FROM AUTHOR]

It is the journal that accepted my very first paper, on Busulfan in children, and it has always been a journal that somehow manages to publish the most original and creative papers of all clinical pharmacology journals out there. I did not know Jim Ritter, but I did know Adam, and surely, if BJCP and the BPS had appointed him as EiC, then this journal must not only be creative, original, and of the highest quality but also modern and continuously rejuvenating itself while at the same time staying loyal to its principles. One of the key aspects of these newer subjects is that they were all initiated by either authors or editorial board members, and at BJCP, we believe that this is the way it should be: "BJCP, a journal of the people, by the people, for the people.". [Extracted from the article]

The British Journal of Clinical Pharmacology's March issue highlights the incorporation of Artificial Intelligence (AI) into clinical pharmacology research, education, patient care, drug development, and dissemination. The issue also features papers on the side effects of drugs, including sex differences in serious adverse drug reactions, predicting adverse drug reactions in neonates, and a program for reporting adverse drug reactions in children and young adults. Additionally, the issue discusses inappropriate prescribing, standardization in pharmacovigilance efforts for pregnancy and breastfeeding, and the effects of isotretinoin on metabolizing enzymes. The author encourages readers to explore the editorial and all the papers on AI and clinical pharmacology. [Extracted from the article]

The British Journal of Clinical Pharmacology has released its latest issue highlights, showcasing a collection of interesting papers that highlight the complexity of drug studies. One paper explores the ins and outs of neurokinin1 receptor antagonism in nausea and vomiting, providing valuable insights for drug development. Another paper investigates the unintended consequences of pharmacovigilance interventions, shedding light on the importance of studying these effects. Additionally, there are studies on a new drug for spinal cord injury, the use of alkaline phosphatase in kidney transplantation, and the clinical pharmacokinetics of oxytocin for preventing postpartum hemorrhage. Despite the challenges of the past year, the journal continues to publish intriguing research and will celebrate its 50th anniversary next year. [Extracted from the article]

We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions. [ABSTRACT FROM AUTHOR]

The British Journal of Clinical Pharmacology has released its October issue, which features a themed section on Pharmacological Considerations for Trans and Gender Diverse Populations. The issue also includes other notable papers, such as a study on the effects of a beta-2-agonist on cerebral metabolism in Parkinson's disease patients and a case report on the treatment of pregnant breast cancer patients with erlotinib. The Editor-in-Chief expresses gratitude to the contributors and highlights the hard work that goes into each issue. The journal typically does not publish case reports, but makes exceptions for exceptional ones. [Extracted from the article]

A biosimilar is a high quality biological medicine shown to be in essence the same as an original product. The European Medicines Agency (EMA) paved the way in the regulatory arena by creating a safeguarding framework for the development of biosimilars. Biosimilar is thus a regulatory term that alludes to the evidence-based studies required to demonstrate such very high similarity. They are therefore not innovative products but the pathway laid down by the EMA for their approval represented a new paradigm. This has brought some confusion and has cast doubts among healthcare professionals about the scientific evidence behind their authorization. Many papers have been published to clarify the concept, and to reassure those professionals, but misconceptions frequently still arise. Unfortunately, this prevents biosimilars from deploying their full therapeutic added value. This paper is intended to approach those misconceptions from a new angle, by explaining what a biosimilar is not...and why. A biosimilar is neither a generic, nor an original product. It is not a biobetter or a 'stand-alone'. Therefore, it should not be managed as such therapeutically, commercially or from a healthcare policy viewpoint. The EMA's criteria were acknowledged by other agencies, but a significant regulatory gap with a vast majority of regulatory bodies still remains. This leaves room for the so-called non-original biologics (NOB), i.e. non-biosimilar biologics, to be launched in many regions. Raising awareness of what a biosimilar is and what it is not, will generate trust in biosimilars among healthcare professionals and will ultimately benefit patients [ABSTRACT FROM AUTHOR]

In order to reduce the numbers of medication errors (MEs) that cause adverse reactions (ARs) many authors have tried to identify patient-related risk factors. However, the evidence remains controversial. The aim was to review systematically the evidence on the relationship between patient-related risk factors and the risk of serious ARs. A systematic search in Pubmed, Embase, Cochrane Systematic Reviews, Psychinfo and SweMed+ was performed. Included full text articles were hand searched for further references. Peer reviewed papers including adults from primary and secondary healthcare were included if they clearly defined seriousness of the ARs and described correlations to risk factors by statistical analysis. A total of 28 studies were identified including 85 212 patients with 3385 serious ARs, resulting in an overall frequency of serious ARs in 4% of patients. Age, gender and number of drugs were by far the most frequently investigated risk factors. The total number of drugs was the most consistent correlated risk factor found in both univariate and multivariate analyses. The number of drugs is the most frequently documented independent patient-related risk factor for serious ARs in both the general adult population as well as in the elderly. The existing evidence is however conflicting due to heterogeneity of populations and study methods. The knowledge of patient-related risk factors for experiencing ARs could be used for electronic risk stratification of patients and thereby allocation of healthcare resources to high risk patients. [ABSTRACT FROM AUTHOR]

Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico‐legal challenges that have remained entrenched in the post‐diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and ‐dynamic understanding of medication use in pregnancy. [ABSTRACT FROM AUTHOR]

The article reports that the pharmacometric models are powerful tools that can be used for a variety of purposes in clinical pharmacology, drug development and dose individualization. It mentions that different types of pharmacometric models serve different purposes and their clinical utility is dependent on this context. It states that the article demonstrates that the previously published model can be used to predict midazolam doses in children but not in preterm neonates or adults.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Industry-funded studies tend to emphasize favourable beneficial effects of the sponsor's product, but we do not know if reports of adverse effects are downplayed. • Pharmaceutical companies are required to collate and accurately report adverse effects data in order to fulfil regulatory requirements. WHAT THIS STUDY ADDS • The bias found in the studies looking at the association between industry funding and reporting of beneficial effects may not be as prominent when considering adverse effects data. • Industry-funded studies do not appear to differ from non-industry-funded studies in reporting the raw adverse effects data, but the interpretation and conclusions may be slanted to favour the sponsor's product. • Readers of industry-funded studies should critically examine the raw safety data themselves rather than be swayed by the authors' interpretation. AIM To investigate whether adverse effects data for the sponsor's product are presented more favourably in pharmaceutical industry-funded studies than in non-industry-funded studies. METHODS We conducted a systematic review of methodological evaluations that had assessed the relationship between industry funding and the reported risk of adverse effects. Searches were undertaken in 10 databases and supplemented with other sources of information such as handsearching, citation searching, checking conference proceedings and discussion with experts. Two reviewers independently screened the records and carried out data extraction for potentially relevant papers. We included studies that compared the results and interpretation of the adverse effects data according to funding source (e.g. adverse effects data in pharmaceutical industry research vs. data from nonprofit organizations, or from one manufacturer vs. another). Methodological evaluations were excluded if categories of funding source were not explicitly specified by the researchers, and if we were uncertain that industry-funded studies were present in the evaluation. RESULTS The search strategy yielded 4069 hits, of which six methodological evaluations met our inclusion criteria. One survey of 370 trials covering a wide range of topics found that trials with industry sponsors had more complete reporting of adverse effects compared with non-industry-funded trials, whereas another survey of 504 inhaled corticosteroid studies showed no apparent difference after confounding factors were adjusted for. In contrast, we found evidence from post hoc subgroup analyses involving two products where the likelihood of harm was of a lower magnitude in manufacturer-funded studies compared with nonmanufacturer-funded studies. There is also evidence from four methodological evaluations that authors with industry funding were more likely than authors without pharmaceutical funding to interpret and conclude that a drug was safe, even among studies that did find a statistically significant increase in adverse effects for the sponsored product. CONCLUSIONS Our review indicates that industry funding may not be a major threat to bias in the reporting of the raw adverse effects data. However, we are concerned about potential bias in the interpretation and conclusions of industry-funded authors and studies. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several comparative measures (ratios, differences, or the number needed to treat) are used to express the effect of a drug or another intervention. • These measures can vary in the way they are affected by the background risk measured from the reference group. WHAT THIS STUDY ADDS? • This paper reviews the formulation, interpretation and limitations of measures of effect. • We describe a little-known parameter, the attained effect or clinical result ratio, a positive reformulation of the relative risk difference, and suggest how available parameters can be best used to summarize results of studies of the effect of drugs. AIMS Measures to compare two drugs are often affected by the background risk in the reference group; a ceiling effect results when the background risk is small. We review measures of the effect of drugs, including a special formulation of the relative risk difference, the attained effect or clinical result ratio, that addresses background risk and ceiling effect. METHODS Existing measures are the risk and odds ratios, the absolute and relative risk differences, and the number needed to treat. The attained effect is defined as the observed gain in success (the difference of proportion of success between the two interventions), divided by the maximum attainable gain, the maximum proportion of success one can expect. We illustrate the relationship between these measures with published results of two meta-analyses. RESULTS In studies of the effectiveness of cell salvage, the baseline risk ranged between 8 and 95%. This variability affected the risk difference and number needed to treat, while the attained effect, with a ceiling residual risk of 2%, showed that the gain in success was half the maximum attainable gain. In studies of the effectiveness of therapy in patients infected by the human immunodeficiency virus, where the baseline risk was less variable, and there was no ceiling effect, the maximum attained effect indicated that the gain could be much smaller. CONCLUSION The attained effect, interpreted as the proportion of effectiveness that remains to gain for future interventions, can usefully complete the number needed to treat as a clinically informative effect measure. [ABSTRACT FROM AUTHOR]

The article presents instruction for authors for submission of their reports in the "British Journal of Clinical Pharmacology."

Specifications on the two-period cross-over clinical trial. Ability of the trial to economize the number of subjects needed; Identification of advantages and disadvantages of the clinical trial; Likelihood of the use of difference from baseline rather than absolute values to increase variability.

The article presents the author's insights concerning the developments in clinical pharmacology from 1974-2014. It highlights the research articles published in the journal which focused on pharmacodynamics, pharmacokinetics, drug metabolism, therapeutics, and analytical methodology. It cites the changes which include changes in intellectual approach and theory and advances that have occurred in some areas of therapeutics.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1β, by central and peripheral immune cells. Il-1β has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS • Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/pharmacodynamic model for LPS-stimulated ATP-induced Il-1β production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. AIMS This paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODS Escalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1β production in blood were evaluated. RESULTS Drug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1β as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study ( n= 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSION The model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development. [ABSTRACT FROM AUTHOR]

The variability of drug response in different patients can be caused by various factors including age, change in renal function, co-medication and genotype. Traditionally, these personal variables are considered by clinicians prior to issuing a prescription. This paper provides an overview of a process to individualize prescribing for a patient with an emphasis on how to train (learning) clinicians in skillful rational prescribing. For this purpose the 6STEP methodology, a concept-based learning strategy to achieve a structured therapeutic plan, has been introduced. In contrast to older educational approaches which focused primarily on the drugs or the process of prescribing, the 6STEP is a patient-centred method resulting in individualized therapy. The six interlinked steps provide the (training) prescriber with a structured framework that facilitates a rationalized therapeutic decision by focusing on the individual patient parameters that influence drug response. Educational tools for rational prescribing involve understanding of basic and clinical pharmacological principles, practicing to write 6STEP therapeutic plans, learning from feedback sessions on these plans and actively obtaining up to date information on drugs and therapeutic standards from online resources. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Junior doctors feel poorly prepared by their training in Clinical Pharmacology and Therapeutics and commonly make prescribing errors. • Since 1993 the General Medical Council's guidance on undergraduate medical education ‘Tomorrow's Doctors’ has emphasized the integration of Clinical Pharmacology and Therapeutics teaching within the medical curriculum. • With the publication of a new version of Tomorrow's Doctors in 2009, medical schools will be further revising their Clinical Pharmacology and Therapeutics teaching. WHAT THIS STUDY ADDS • Although we know what the recommendations for undergraduate teaching of Clinical Pharmacology and Therapeutics teaching are, there are no published data describing what is currently happening in UK medical schools. • This paper describes the course structures, volume and range of teaching and assessment of Clinical Pharmacology and Therapeutics in the UK in 2009. • Our data provide a foundation for schools looking to revise the Clinical Pharmacology and Therapeutics Teaching in the light of Tomorrow's Doctors 2009. AIM To describe the current structure, delivery and assessment of Clinical Pharmacology and Therapeutics (CPT) teaching in UK medical schools. METHODS An online questionnaire was distributed to the person with overall responsibility for CPT teaching at all UK medical schools in June 2009. RESULTS Thirty of the 32 UK medical schools responded. 60% of schools have a CPT course although in 72% this was an integrated vertical theme. At 70% of schools pharmacologists have overall responsibility for CPT teaching (clinical 67%, non-clinical 33%); at 20% teaching is run by a non-specialist clinician and at 7% by a pharmacist. Teaching is commonly delivered by NHS clinicians (87%) and clinical pharmacists (80%) using lectures (90%) but additionally 50% of schools use e-Learning and 63% have a student formulary. CPT is assessed throughout the curriculum at many schools through written, practical examinations and course work. 90% of schools have specific CPT content in their written examinations. 90% of respondents believed that their students were ‘fairly’ to ‘well’ prepared for the foundation year but only 37% of schools gather data on the competence of their graduates. CONCLUSIONS CPT teaching in UK medical schools is very diverse. Most schools do not assess the performance of their graduates as prescribers and there is a lack of evidence that many of the teaching approaches employed are suitable for the development of prescribing skills. It is vital that developments in CPT teaching are driven by validated, real-world assessments of the prescribing skills of medical students and newly qualified doctors. [ABSTRACT FROM AUTHOR]

What is already known about this subject • We recently proposed an algorithm to assess the degree of therapeutic innovation of new therapeutic agents. It was based on the disease seriousness, the availability of previous treatments and the extent of the therapeutic effect, and was applied to all therapeutic agents approved by the EMEA in the period 1995–2003. • A low percentage (32%) of important therapeutic innovation was found. This figure may be an underestimate of the actual level of innovation, because common biotechnological products, such as recombinant human insulins, must follow the centralized procedure. What this study adds • Details for each agent, focusing on the comparison of the degree of therapeutic innovation between biotechnological and nonbiotechnological therapeutic agents approved by EMEA during the its first decade of activity (1995–2004). The underlying hypothesis was that the latter have a higher degree of innovation because they followed the centralized procedure on the assumption that they are innovative. • The percentage of important therapeutic innovation was low not only for biotechnological products (25%), as expected because they include many already known products such as insulins, but also for nonbiotechnological therapeutic agents (29%). Aims In a previous paper, we proposed an algorithm to assess the degree of therapeutic innovation of the agents approved by the European centralized procedure, which must be followed by biotechnological products and is optional for drugs claimed as innovative. A low overall degree of therapeutic innovation (about 30%) was found. This figure may be an underestimate of the actual level of innovation, because common biotechnological products, such as recombinant human insulins, must follow this procedure. To test the hypothesis that therapeutic innovation prevails among nonbiotechnological products, we evaluated separately the degree of therapeutic innovation of biotechnological vs. nonbiotechnological agents in the first decade of European Medicines Agency activity, also studying a possible time trend. Methods We assessed, for each drug: (i) the seriousness of the target disease, (ii) the availability of previous treatments, and (iii) the extent of therapeutic effect according to the previously proposed algorithm. Results Our analysis considered 251 medicinal products corresponding to 198 active substances, classified according to four main areas as therapeutic agents (88.9%), diagnostics (5.5%), vaccines (5.1%) and life-style drugs (0.5%). Among all therapeutic agents, 49 out of 176 agents (28%) were classified as having an important degree of therapeutic innovation. Fifteen out of 60 biotechnological therapeutic agents were considered important therapeutic innovations (25%), whereas this figure was 29% for nonbiotechnological agents. Conclusions Among active substances claimed as innovative by the manufacturers, only a minority deserve this definition according to our algorithm. [ABSTRACT FROM AUTHOR]

The invention of the internet and the world-wide web was a landmark that has affected many aspects of everyday life, but is so recent and dynamic that many of its potential uses are still being explored. Aside from its purely commercial use as a virtual pharmacy (e-commerce), the internet is useful in at least three aspects related to clinical pharmacology: communication, training and research. In this paper we briefly review several internet applications related to clinical pharmacology and describe, as an example, the logistics of a multicentre research collaboration related to the promotion of rational drug use in the prevention of postpartum haemorrhage. [ABSTRACT FROM AUTHOR]

Presents the 2002 report of the editors of the 'British Journal of Clinical Pharmacology.' Submissions; Circulation statistics; Operations of the Australasian office.

Aims: The UK Prescribing Safety Assessment was modified for use in Australia and New Zealand (ANZ) as the Prescribing Skills Assessment (PSA). We investigated the implementation, student performance and acceptability of the ANZ PSA for final‐year medical students. Methods: This study used a mixed‐method approach involving student data (n = 6440) for 2017–2019 (PSA overall score and 8 domain subscores). Data were also aggregated by medical school and included student evaluation survey results. Quantitative data were analysed using descriptive and multivariate analyses. The pass rate was established by a modified Angoff method. Thematic analyses of open‐ended survey comments were conducted. Results: The average pass rate was slightly higher in 2017 (89%) which used a different examination to 2018 (85%) and 2019 (86%). Little difference was identified between schools for the PSA overall performance or domain subscores. There was low intercorrelation between subscores. Most students provided positive feedback about the PSA regarding the interface and clarity of questions, but an average of 35% reported insufficient time for completion. Further, 70% on average felt unprepared by their school curricula for the PSA, which is in part explained by the low prescribing experience; 69% reported completing ≤10 prescriptions during training. Conclusion: The ANZ PSA was associated with high pass rates and acceptability, although student preparedness was highlighted as a concern for further investigation. We demonstrate how a collaboration of medical schools can adapt a medical education assessment resource (UK PSA) as a means for fulfilling an unmet need. [ABSTRACT FROM AUTHOR]

Aims: The new modified‐release formulation of tegoprazan, a novel potassium‐competitive acid blocker, is expected to improve the management of acid‐related disease, including nocturnal acid breakthrough, by prolonging the duration of acid suppression. This study aimed to explore the pharmacokinetics (PK) and pharmacodynamics (PD) of various combinations of tegoprazan with immediate‐release (IR) and delayed‐release (DR) formulations. Methods: A three‐cohort, open‐label, randomized, single‐dose, three‐treatment, six‐sequence, three‐period crossover study was conducted. Various combinations of tegoprazan IR and DR formulations (50, 75 or 100 mg) were administered orally once per period. The 24‐h intragastric pH was monitored before and after each administration. PK blood samples were collected for up to 48 h. PK and PD were compared among treatments. Results: Eighteen healthy Korean subjects completed the study. All treatment groups showed intragastric pH above 4 approximately 1 h following tegoprazan administration. Among the various combinations, the IR and DR combination at a 1:1 ratio induced greater gastric acid suppression (%Time pH ≥ 4) than IR alone in each dose group, both for 24 h (50 mg; 59% vs. 52%, P =.2188, 95% confidence interval [CI] −6.92–22.27, 100 mg; 85% vs. 70%, P <.05, 95% CI 8.92–22.19) and at night (50 mg; 27% vs. 16%, P =.1563, 95% CI −11.79–37.71, 100 mg; 77% vs. 49%, P <.05, 95% CI 16.14–42.98), with similar systemic exposure. Conclusions: The combinatorial tegoprazan in the IR and DR 1:1 ratio formulation was found to induce stronger gastric acid suppression throughout the day and at night, compared to the conventional IR formulation. [ABSTRACT FROM AUTHOR]

Aims: In 2017, two distinct interventions were implemented in Ireland and England to reduce prescribing of lidocaine medicated plasters. In Ireland, restrictions on reimbursement were introduced through implementation of an application system for reimbursement. In England, updated guidance on items which should not be routinely prescribed in primary care, including lidocaine plasters, was published. This study aims to compare how the interventions impacted prescribing of lidocaine plasters in these countries. Methods: We conducted an interrupted time‐series study using general practice data. For Ireland, monthly dispensing data (2015–2019) from the means‐tested General Medical Services (GMS) scheme was used. For England, data covered all patients. Outcomes were the rate of dispensings, quantity and costs of lidocaine plasters, and we modelled level and trend changes from the first full month of the policy/guidance change. Results: Ireland had higher rates of lidocaine dispensings compared to England throughout the study period; this was 15.22/1000 population immediately pre‐intervention, and there was equivalent to a 97.2% immediate reduction following the intervention. In England, the immediate pre‐intervention dispensing rate was 0.36/1000, with an immediate reduction of 0.0251/1000 (a 5.8% decrease), followed by a small but significant decrease in the monthly trend relative to the pre‐intervention trend of 0.0057 per month. Conclusions: Among two different interventions aiming to decrease low‐value lidocaine plaster prescribing, there was a substantially larger impact in Ireland of reimbursement restriction compared to issuing guidance in England. However, this is in the context of much higher baseline rates of use in Ireland compared to England. [ABSTRACT FROM AUTHOR]

Aims: Animal studies suggest that methylphenidate treatment for around 3 months may lead to less mineralized and weaker appendicular bones. A systematic review was conducted to summarize the evidence from observational studies, and a self‐controlled case series study was used to compare the risk before and after treatment initiation. Methods: Literature search was conducted using PubMed, Embase and the Cochrane Library to identify observational studies on methylphenidate and fractures. We also conducted a self‐controlled case series study with individuals aged 5–24 years who received methylphenidate treatment and experienced fractures from 2001 to 2020 in Hong Kong. Incidence rate ratios and 95% confidence intervals were calculated by comparing the incidence rate in the methylphenidate‐exposed period compared with nonexposed period. Results: Six cohort studies and 2 case–control studies were included in the systematic review. For all‐cause fractures, studies found a 39–74% lower risk in treated‐attention deficit hyperactivity disorder (ADHD) group compared with untreated ADHD but no difference between stimulants and nonstimulants. Differences between sexes and treatment duration were also found—significant results were shown in males and those with longer treatment duration. Among 43 841 individuals with ADHD medication before the year 2020, 2023 were included in the self‐controlled case series analysis. The risks of fractures were lower by 32–41% in different treatment periods when compared with 6 months before treatment initiation. Conclusion: Methylphenidate treatment may lower the risk of all‐cause fractures from both study designs; however, further evidence is needed about the treatment duration and sex effect. Conclusions on stress fractures are not yet established, and further research is required. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to compare the Liverpool Causality Assessment Tool vs. Naranjo Scale for screening suspected adverse drug reaction (ADR) cases. Methods: We retrospectively reviewed patient charts with a history of suspected ADR, scored using both tools, and determined how each correlates with laboratory and other investigations. A total of 924 charts from the Clinical Pharmacology Clinic at the London Health Sciences Centre were reviewed, and 529 charts contained objective findings to support or against the diagnosis of ADR. The participant age ranged from 1 month to 93 years. We determined that the sensitivity (SN) and specificity (SP) of Liverpool and Naranjo tools for predicting ADRs with scores ranging from Possible to Definite were considered positive and Unlikely/Doubtful as negative for ADR. These results were confirmed by laboratory or clinical (re‐challenge) testing in 529 cases. Results: Liverpool causality tool had SN of 97.2 ± 2.4% and SP of 2.3 ± 1.57%. The positive (PPV) and negative predictive values (NPV) were 34.1 and 61.5%, respectively. The Naranjo Scale had SN of 81.2 ± 5.69% and SP of 13.2 ± 3.56%. PPV and NPV were 32.7 and 57.5%, respectively. Conclusion: The Liverpool Causality Assessment Tool is a more sensitive tool than the Naranjo Scale in the assessment of possible ADRs, but both tools have poor SP. The Liverpool Tool can be a useful screening tool in settings where other tests may not be readily available. However, the low PPV and NPV of both tools suggest that to pursue further testing is needed to confirm or deny an ADR. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to develop a population pharmacokinetic (PK) model to simultaneously describe both total and unbound concentrations of ciprofol and its major glucuronide metabolite, M4, and to link it to the population pharmacodynamics (PD) model in subjects with various renal functions. Methods: A total of 401 and 459 pairs of total and unbound plasma concentrations of ciprofol and M4, respectively, as well as 2190 bispectral index (BIS) data from 24 Chinese subjects with various renal functions were available. Covariates that may potentially contribute to the PK and PD variability of ciprofol were screened using a stepwise procedure. The optimal ciprofol induction dosing regimen was determined by model‐based simulations. Results: The PK of unbound ciprofol could best be described by a three‐compartment model, while a two‐compartment model could adequately describe unbound M4 PK. The concentrations of total and unbound ciprofol and M4 were linked using a linear protein binding model. The relationship between plasma concentrations of ciprofol and BIS data was best described by an inhibitory sigmoidal Emax model with a two‐compartment biophase distribution compartment. Hemoglobin was the identified covariate determining the central compartment clearance of ciprofol; uric acid was a covariate affecting the central compartment clearance of M4 and protein binding rate, kB. The included covariates had no effect on the PD of ciprofol. Simulation results indicated that the label‐recommended dose regimen was adequate for anaesthesia induction. Conclusions: The developed model fully characterized the population PK and PD profiles of ciprofol. No dose adjustment is required in patients with mild and moderate renal impairment. [ABSTRACT FROM AUTHOR]

Aims: Adverse drug reactions (ADRs) represent a significant public health burden. There are few data on fatal ADRs in children. This population is particularly at risk due to metabolic and physiological immaturity, frequent off‐label drug use and limited paediatric clinical pharmacology studies. The study investigated the main characteristics of drug‐related deaths registered in World Health Organization pharmacovigilance database, during the past decade. Methods: Fatal outcomes registered between 2010 and 2019 in children (<18 y) and reported by physicians were investigated. Age, sex and suspected drugs were described and disproportionality analyses investigated differences according to sex, age and continents with calculation of reporting odds ratio and its 95% confidence interval. Results: Among the 1 198 560 reports registered in children, 1585 (0.13%) were fatal. They occurred mainly in boys, aged 28 days–23 months. Reports mostly came from the Americas and Europe and involved, besides anti‐infectious drugs (mainly vaccines), central nervous system (vigabatrin, paracetamol, methylphenidate...) and antineoplastic/immunomodulating (mainly thalidomide) and cardiovascular (mainly bosentan) drugs without major differences between boys and girls. Large differences were found according to continents and age. The risk of reporting was higher in boys, in children aged <23 months, in the Americas and Africa. Conclusion: Fatal ADRs represented a small part (around 1/1000) of total registered ADRs, occurred more frequently in boys and during the first 2 years of life. Beside anti‐infectious drugs (vaccines), neuropsychiatric drugs were the most frequently involved, with large differences according to continents and classes of age. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to investigate how the prescribing knowledge and skills of junior doctors in the Netherlands and Belgium develop in the year after graduation. We also analysed differences in knowledge and skills between surgical and nonsurgical junior doctors. Methods: This international, multicentre (n = 11), longitudinal study analysed the learning curves of junior doctors working in various specialties via three validated assessments at about the time of graduation, and 6 months and 1 year after graduation. Each assessment contained 35 multiple choice questions (MCQs) on medication safety (passing grade ≥85%) and three clinical scenarios. Results: In total, 556 junior doctors participated, 326 (58.6%) of whom completed the MCQs and 325 (58.5%) the clinical case scenarios of all three assessments. Mean prescribing knowledge was stable in the year after graduation, with 69% (SD 13) correctly answering questions at assessment 1 and 71% (SD 14) at assessment 3, whereas prescribing skills decreased: 63% of treatment plans were considered adequate at assessment 1 but only 40% at assessment 3 (P <.001). While nonsurgical doctors had similar learning curves for knowledge and skills as surgical doctors (P =.53 and P =.56 respectively), their overall level was higher at all three assessments (all P <.05). Conclusion: These results show that junior doctors' prescribing knowledge and skills did not improve while they were working in clinical practice. Moreover, their level was under the predefined passing grade. As this might adversely affect patient safety, educational interventions should be introduced to improve the prescribing competence of junior doctors. [ABSTRACT FROM AUTHOR]

AIMS The aim of this study was to identify what definitions have been published for the term 'deprescribing', and determine whether a unifying definition could be reached. A secondary aim was to uncover patterns between the published definitions which could explain any variation. METHODS Systematic literature searches were performed (earliest records to February 2014) in MEDLINE, Embase, CINAHL, Informit, Scopus and Google Scholar. The terms deprescrib* or de-prescrib* were employed as a keyword search in all fields. Conventional content analysis and word frequencies were used to identify characteristics of the definitions. Network analysis was conducted to visualize characteristic distribution across authors and articles. RESULTS Following removal of duplicates, 231 articles were retrieved, 37 of which included a definition. Eight characteristics of the definitions were identified: use of the term stop/withdraw/cease/discontinue (35 articles), aspect of prescribing included e.g. long termtherapy/inappropriatemedications (n = 18), use of the term 'process' or 'structured' (n = 13), withdrawal is planned/supervised/judicious (n = 11), involving multiple steps (n = 7), includes dose reduction/substitution (n = 7), desired goals/outcomes described (n = 5) and involves tapering (n = 4). Network analysis did not reveal patterns responsible for variations in previously used definitions. CONCLUSIONS These findings show that there is lack of consensus on the definition of deprescribing. This article proposes the following definition: 'Deprescribing is the process of withdrawal of an inappropriate medication, supervised by a health care professional with the goal of managing polypharmacy and improving outcomes'. This definition has not yet been externally validated and further work is required to develop an internationally accepted and appropriate definition. [ABSTRACT FROM AUTHOR]

Comments on the celebration of the 25th anniversary of the foundation of the 'British Journal on Clinical Pharmacology.' Impact of the relocation of office on operations; Compositions of the journal; Topics of important papers published in the journal.

Aims: Sixty‐four million pharmacy‐filled multicompartment medication compliance aids (MCAs) are dispensed by pharmacies in England each year. Despite the widespread use of MCAs and evidence that their use may be associated with harm there is no national consensus regarding MCA provision by acute hospital Trusts in England. The aim was to determine current practice for initiation and supply of MCAs in acute hospital Trusts in England and the potential consequences for patients and hospitals. Methods: A 26‐item survey was distributed to all acute hospital Trusts in England. The questionnaire covered: policy, initiation, supply and review of MCAs; alternatives offered; and pharmacy staffing and capacity related to MCAs. Results: Seventy‐two out of 138 (52%) Trusts responded to the survey: 70 Trusts responded regarding policy for MCA provision, with 60 (86%) having a policy regarding this; 33/55 (60%) that supplied MCAs on discharge supplied a different prescription length for MCA vs. non‐MCA prescriptions; 49/55 (89%) Trusts provided only 1 brand of MCA; 47/55 (85%) MCA‐supplying Trusts identified frequent difficulties with MCAs and 13/55 (24%) reported employing staff specifically to complete MCAs; and 30/35 (86%) MCA‐initiating Trusts had an assessment process for initiation, with care agency request reportedly the most common reason for initiation. Conclusion: There is a lack of a national approach to MCA provision and initiation by acute hospital Trusts in England. This leads to significant variation in care and has the potential to put MCA users at an increased risk of medication‐related harm. [ABSTRACT FROM AUTHOR]

Aim The aim of this review was to summarize the prevalence, frequency and comparative value of information on the adverse events of healthcare interventions from user comments and videos in social media. Methods A systematic review of assessments of the prevalence or type of information on adverse events in social media was undertaken. Sixteen databases and two internet search engines were searched in addition to handsearching, reference checking and contacting experts. The results were sifted independently by two researchers. Data extraction and quality assessment were carried out by one researcher and checked by a second. The quality assessment tool was devised in-house and a narrative synthesis of the results followed. Results From 3064 records, 51 studies met the inclusion criteria. The studies assessed over 174 social media sites with discussion forums (71%) being the most popular. The overall prevalence of adverse events reports in social media varied from 0.2% to 8% of posts. Twenty-nine studies compared the results from searching social media with using other data sources to identify adverse events. There was general agreement that a higher frequency of adverse events was found in social media and that this was particularly true for 'symptom' related and 'mild' adverse events. Those adverse events that were under-represented in social media were laboratory-based and serious adverse events. Conclusions Reports of adverse events are identifiable within social media. However, there is considerable heterogeneity in the frequency and type of events reported, and the reliability or validity of the data has not been thoroughly evaluated. [ABSTRACT FROM AUTHOR]

Aims A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children. Methods MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed. Results From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants. Conclusions Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base. [ABSTRACT FROM AUTHOR]

CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3‐kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA‐related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signalling pathway. Compassionate use of low‐dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with life‐threatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low‐dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease‐specific features of PROS. [ABSTRACT FROM AUTHOR]