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Aims: Information on breastfeeding and safety of biologics in infants is lacking due to difficulties in case collection. We evaluated methods for determining the concentration of biologics in breast milk using a dry filter method that can simplify the collection, storage and transport of breast milk. Methods: To generate dried filter paper (DFP) samples, approximately 30 μL of breast milk was placed onto a Whatman 903 card and punched out. After extraction, the supernatant was measured using an enzyme‐linked immunosorbent assay. Three concentrations of each drug were prepared in liquid breast milk (LBM) and DFP samples to determine their stability up to 28 days after storage at 2–8°C or −20°C for LBM and 25 ± 5°C for DFP. LBM and DFP samples were also provided by nursing mothers using biologics during lactation, and drug concentrations in both samples were compared. The agreement between the two measurement methods was confirmed by Bland–Altman analysis. Results: Breast milk was provided by 12 mothers who used biologics (tocilizumab, abatacept, etanercept, golimumab, sarilumab and belimumab). The coefficients of variation for within‐run and between‐run precision for the six drugs were within 15% for both LBM and DFP, and accuracy was within 90%–110% of the quality controls. After 28 days, concentrations remained at more than 90%. The difference between the values obtained by each method was within the acceptable range of error (−12.1 to +16.6 ng/mL). Conclusions: A method for determining the concentration of biologics using DFP is expected to help improve pharmacotherapy for lactating women. [ABSTRACT FROM AUTHOR]

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease‐ and/or target organ‐specific examples. Identifying and testing PD targets and effects in special populations, and application of age‐ and/or population‐specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD‐related as well as drug safety‐related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development. [ABSTRACT FROM AUTHOR]

Children frequently respond differently to therapies compared to adults. Differences also exist between paediatric age groups for pharmacokinetics and pharmacodynamics in both efficacy and safety. Paediatric pharmacovigilance requires an understanding of the unique aspects of children with regard to, for example, drug response, growth and development, clinical presentation of adverse drug reactions (ADRs), how they can be detected and population‐specific factors (e.g., more frequent use of off‐label/unlicensed drugs). In recognition of these challenges, a group of experts has been formed in the context of the conect4children (c4c) project to support paediatric drug development. This expert group collaborated to develop methodological considerations for paediatric drug safety and pharmacovigilance throughout the life‐cycle of medicinal products which are described in this article. These considerations include practical points to consider for the development of the paediatric section of the risk management plan (RMP), safety in paediatric protocol development, safety data collection and analysis. Furthermore, they describe the specific details of post‐marketing pharmacovigilance in children using, for example, spontaneous reports, electronic health care records, registries and record‐linkage, as well as the use of paediatric pharmacoepidemiology studies for risk characterisation. Next the details of the assessment of benefit–risk and challenges related to medicinal product formulation in the context of a Paediatric Investigation Plan (PIP) are presented. Finally, practical issues in paediatric signal detection and evaluation are included. This paper provides practical points to consider for paediatric pharmacovigilance throughout the life‐cycle of medicinal products for RMPs, protocol development, safety data collection and analysis and PIPs. [ABSTRACT FROM AUTHOR]

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]

The safety and efficacy of pharmacotherapy in children, particularly preterms, neonates and infants, is limited by a paucity of good‐quality data from prospective clinical drug trials. A specific challenge is the establishment of valid biomarkers. OMICs technologies may support these efforts by complementary information about targeted and nontargeted molecules through systematic characterization and quantitation of biological samples. OMICs technologies comprise at least genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics in addition to the patient's phenotype. OMICs technologies are in part hypothesis‐generating, allowing an in depth understanding of disease pathophysiology and pharmacological mechanisms. Application of OMICs technologies in paediatrics faces major challenges before routine adoption. First, developmental processes need to be considered, including a subdivision into specific age groups as developmental changes clearly impact OMICs data. Second, compared to the adult population, the number of patients is limited as are the type and amount of necessary biomaterial, especially in neonates and preterms. Thus, advanced trial designs and biostatistical methods, noninvasive biomarkers, innovative biobanking concepts including data and samples from healthy children, as well as analytical approaches (eg liquid biopsies) should be addressed to overcome these obstacles. The ultimate goal is to link OMICs technologies with innovative analysis tools, such as artificial intelligence at an early stage. The use of OMICs data based on a feasible approach will contribute to the identification complex phenotypes and subpopulations of patients to improve the development of medicines for children with potential economic advantages. [ABSTRACT FROM AUTHOR]

Older people are often affected by impaired organ and bodily functions resulting in multimorbidity and polypharmacy, turning them into the main user group of many medicines. Very often, medicines have not specifically been developed for older people, causing practical medication problems for them like limited availability of easy to swallow formulations, easy to open packaging and dosing instructions for enteral administration. In 2020, the European Medicines Agency (EMA) published a reflection paper 'Pharmaceutical development of medicines for use in the older population', which discusses how the emerging needs of an ageing European population can be addressed by medicines regulation. The paper intends to help industry to better consider the needs of older people during pharmaceutical/clinical medicines development by summarising data on the most relevant topics, providing early suggestions on how to move forward and prompting expert discussions and studies into knowledge gaps. Topics include patient acceptability, (dis)advantages of an administration route, formulation, dosage form, packaging, dosing device and user instruction. While the paper is directed at older people and the pharmaceutical industry, the reflections are also relevant to younger patients with similar disease‐related needs and of value to other stakeholders parties, e.g., healthcare professionals, academics, patients and caregivers, as the paper makes clear what can be expected from industry and where collaborative work is needed. This commentary provides an overview of the different steps in the development of the reflection paper, discusses points considered most controversial and/or subject to (multidisciplinary) expert discussions and indicates their value for real world clinical practice. [ABSTRACT FROM AUTHOR]

Increased global longevity requires a re‐evaluation of current structures in society to adapt to the consequential demographic shift. As (very) old people are prone to impaired human organ and body functions resulting in, for example, multimorbidity, polypharmacy, hospitalisation and problems in medication management, it is increasingly acknowledged that re‐evaluations should include the suitability of pharmaceutical patient care as one of the cornerstones of public health. Following the 2011 European Medicines Agency (EMA) Geriatric Strategy, in 2017 the EMA published the draft "Reflection paper on the pharmaceutical development of medicines for use in the older population". The draft paper was opened for public consultation and specific attention and feedback (either supportive or with a proposal for revision) was asked on three design aspects: tablet breaking, drug administration through enteral feeding tubes and medication management. Following publication, the draft paper was presented at two public conferences attended by participants from different disciplines. This manuscript is intended to draw the attention of different stakeholder parties to the urgent need to collaborate on the emerging issues arising from increasing longevity and multimorbidity, and especially those associated with pharmaceutical patient care and drug product design, including the need for collaborative research into existing or emerging knowledge gaps. The manuscript focuses on the three aforementioned aspects of pharmaceutical development (tablet breaking, drug administration through enteral feeding tubes and medication management) as these highly relate to medication safety and efficacy and constitute persistent and typical challenges for older people, caregivers and healthcare professionals in daily clinical practice. [ABSTRACT FROM AUTHOR]

Adopted guidelines reflect a harmonised European approach to a specific scientific issue and should reflect the most recent scientific knowledge. However, whilst EU regulations are mandatory for all member states and EU directives must be followed by national laws in line with the directive, EMA guidelines do not have legal force and alternative approaches may be taken, but these obviously require more justification. This new series of the BJCP, developed in collaboration with the EMA, aims to address this issue by providing an annotated version of some relevant EMA guidelines and regulatory documents by experts. Hopefully, this will help in promoting their diffusion and in opening a forum for discussion with our readers. [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]

The Cochrane Library published a systematic review of interventions for paracetamol overdose in 2018.8 The conclusion begins: 'These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available'. Disproportionate effect on child admissions of the change in Medicines and Healthcare Products Regulatory Agency guidance for management of paracetamol poisoning: an analysis of hospital admissions for paracetamol overdose in England and Scotland. Keywords: poisoning; research; toxicology EN poisoning research toxicology 56 57 2 02/01/22 20220101 NES 220101 Clinical Toxicology is one of the core sub-specialities of Clinical Pharmacology and Therapeutics. [Extracted from the article]

I read with interest the paper entitled I The impact of tacrolimus exposure on extra-renal adverse effects in adult renal transplant recipients i that was published in the I Journal i (2019, Vol 85, pp. 516-529). Patients receiving tacrolimus have their doses individualized (based upon tacrolimus trough concentration) and this (at least partially) I normalizes i exposure to account for differences in patient factors. [Extracted from the article]

The Medicines and Healthcare products Regulatory Agency was established in April 2003 by the merger of the Medicines Control Agency (MCA) and the Medical Devices Agency (MDA). This paper describes the scientific and organizational basis for the merger and describes the various challenges facing this new Agency. [ABSTRACT FROM AUTHOR]

The literature on pencil and paper tests and the effects of psychotropic drugs is reviewed. Performance at digit symbol substitution, symbol copying, letter cancellation, arithmetic, logic and cognitive processing with a relatively constant level of triazolam was compared with placebo. Analysis of variance, covariance analysis and principal component analysis were applied to the data. Pencil and paper tests which measure various skills are useful for detecting drug effects. Letter cancellation, arithmetic and DSST appear to be most sensitive, although logic and symbol copying may be useful. [ABSTRACT FROM AUTHOR]

Describes a method of therapeutic drug monitoring of antiepileptic drugs (AED) in blood spots dried on filter paper in outpatient settings. Correlation of AED concentrations in serum and whole blood; Quantification of AED.

Aims: Candidates with disabilities are eligible for reasonable adjustments (RA) while undertaking the national Prescribing Safety Assessment (PSA). The PSA is a novel open‐book, time‐constrained, multiformat assessment that may pose challenges to candidates with dyslexia and other disabilities. Methods: Retrospective cohort analysis of 36 140 UK candidates undertaking first‐sitting of the PSA (2014–2018). Results: Of the 36 140 candidates, 9.1% (3284) were registered for RA. The RA group had lower pass rates (absolute difference 1.94%, 95% confidence interval 1.01–2.87%; P <.001) and assessment scores (1.16 percentage marks, 95% confidence interval 0.83–1.48; P <.001) compared with the non‐RA group. This absolute difference is small relative to overall variability. This difference persists after adjusting for confounding factors (medical school and paper), and was present for all 8 different question types. The attainment gap within each medical school is negatively correlated with the school's overall performance, both in terms of pass rate (P <.001) and scores (P =.01). The RA group were also less likely to perceive the PSA as an appropriate test, having easy to follow layout/presentation or clear/unambiguous questions, even after adjusting for candidate performance. Conclusion: This analysis identifies slight differences in academic performance of candidates requiring RA in a national undergraduate assessment. The study is limited by the unavailability of data on ethnicity, sex, age, diagnosis and time of diagnosis. While further research is required to determine the cause of the attainment gap, this study emphasises the need to maintain a careful review on the fairness and validity of all aspects of the assessment. [ABSTRACT FROM AUTHOR]

Measurement of pre‐dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration—time curve (AUC).However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long‐term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed.In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients. [ABSTRACT FROM AUTHOR]

Aims: Understanding how much healthcare professionals (HCPs) know about medication can help in devising strategies to improve rational medication use. This study aimed to synthesize information on the level of medication knowledge of HCPs in Africa. Method: We performed a systematic literature study in Embase and PubMed. We included original studies quantifying HCPs' medication knowledge, published between 2012 and 2016. We extracted disease focus, country, number and type of HCPs included and all medication‐related knowledge questions and scored the quality of papers. The outcome measure was the percentage of HCPs who correctly answered medication knowledge questions. Results: We identified 64 studies from 12 African countries, comprising 13 911 HCPs, mostly nurses/midwifes and physicians. We extracted 306 medication‐related knowledge questions, and only 52% (SD 28) of HCPs correctly answered them. Knowledge questions were mainly about medication prescribed for communicable diseases (70%), followed by non‐communicable diseases (11%), and family planning/gynaecology (10%). Most papers concluded that there was a considerable medication knowledge gap among HCPs. Conclusion: We found a low level of medication knowledge across different disease areas, countries and HCPs. This underlines the continuous need to strengthen the undergraduate and postgraduate education in (clinical) pharmacology and therapeutics in Africa. [ABSTRACT FROM AUTHOR]

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well‐designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state‐of‐the‐art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science. [ABSTRACT FROM AUTHOR]

The sources of bias in medication adherence research have not been comprehensively explored. We aimed to identify biases expected to affect adherence research and to develop a framework for mapping these onto the phases of adherence (initiation, implementation and discontinuation). A literature search was conducted, key papers were reviewed and a Catalogue of Bias was consulted. The specific biases related to adherence measurement and metrics were mapped onto the phases of adherence using a tabular matrix. Twenty‐three biases were identified, of which 11 were specifically relevant to adherence measures and metrics. The mapping framework showed differences in the numbers and types of biases associated with each measure and metric while highlighting those common to many adherence study designs (e.g., unacceptability bias and apprehension bias). The framework will inform the design of adherence studies and the development of risk of bias tools for adherence research. [ABSTRACT FROM AUTHOR]

Aims Newly graduated doctors write a large proportion of prescriptions in UK hospitals but recent studies have shown that they frequently make prescribing errors. The prescribing safety assessment (PSA) has been developed as an assessment of competence in relation to prescribing and supervising the use of medicines. This report describes the delivery of the PSA to all UK final-year medical students in 2016 (PSA2016). Methods The PSA is a 2-hour online assessment comprising eight sections which cover various aspects of prescribing defined within the outcomes of undergraduate education identified by the UK General Medical Council. Students sat one of four PSA 'papers', which had been standard-set using a modified Angoff process. Results A total of 7343 final-year medical students in all 31 UK medical schools sat the PSA. The overall pass rate was 95% with the pass rates for the individual papers ranging from 93 to 97%. The PSA was re-sat by 261 students who had failed and 80% of those candidates passed. The internal consistency (Cronbach's alpha) of the four papers ranged from 0.74 to 0.77 (standard error of measurement 4.13-4.24%). There was a statistically significant variation in performance between medical school cohorts (F = 32.6, P < 0.001) and a strongly positive correlation in performance for individual schools between PSA2015 and PSA2016 ( r = 0.79, 95% CI 0.61-0.90; P < 0.01). Conclusions PSA2016 demonstrated the feasibility of delivering a standardized national prescribing assessment online. The vast majority of UK final-year medical students were able to meet a prespecified standard of prescribing competence. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to examine the cooccurrence of heightened media attention after the publication of a paper by Skovlund et al in September 2016 on the link between hormonal contraception and depression or mood on adverse drug reaction (ADR) reports in the UK. Methods: A quantitative analysis of relevant newspaper articles published between January 2014 and December 2017 was performed, as well as a content analysis. ADR reports were collected from the Medicines and Healthcare Products Regulatory Agency website and via a Freedom of Information request. A quantitative analysis was performed on ADR reports of hormonal contraceptives for all ADRs and for depressed mood disorders and disturbances. Results: The publication of the Skovlund et al paper did not lead to a peak in relevant newspaper articles, but there was a change in the content of the newspaper articles, which focussed more on the link between hormonal contraceptives and depression or mood. There was an overall increase in ADR reports by women relating to hormonal contraceptives between 2016 and 2017, and for combined contraceptives this was due to an increase in ADR reports of depressed mood disorders and disturbances. Conclusions: The content of media attention appears to affect ADR reporting by women for combined contraceptives. In general, patients report the majority of depressed mood disorders and disturbances ADRs as opposed to health professionals, who report other ADRs. Care providers can anticipate the effect of heightened media attention and help patients when they experience these ADRs. [ABSTRACT FROM AUTHOR]

1Pharmacokinetic parameters of trapidil (an antagonist of platelet derived growth factor) were evaluated in 12 healthy male subjects (study I) and in a group of 10 patients with liver cirrhosis (Child B) and five control subjects, respectively (study II). 2Investigations were carried out after a single dose trapidil (200 mg) and at steady state after application of 200 mg trapidil three times daily for 5 days (study 1) or 4 days (study II). 3 Study I: The concentration-time curves of the terminal elimination phase of trapidil exhibited a slight convexity which might reflect nonlinear kinetics. The AUC of trapidil obtained after the first dose (20.5 [±7.0 s.d.] μg ml−1 h) was markedly higher than the AUC determined at steady state (13.2 [±3.8 s.d.] μg ml−1 h), the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.58-0.73 (point estimator 0.64). 4 Study II: AUC averaged (21.4 [±9.1 s.d.] μg ml−1 h) in controls and (34.4 [±14.9 s.d.] μg ml−1 h) in cirrhotic patients. The 90% confidence intervals for the difference group 1 vs group 2 was 0.95-2.97 (point estimator 1.48, P=0.066). At steady state, AUC averaged (13.7 [±5.7 s.d.] μg ml−1 h) in controls and (20.8 [±6.8 s.d.] μg ml−1 h) in cirrhotic patients (90% confidence intervals group 1 vs group 2: 0.88-2.20 [point estimator 1.45, P=0.05]). As seen in study I, the AUC of trapidil obtained after the first dose was markedly higher than the AUC determined at steady state , the non-parametric 90% confidence intervals of the ratio day 5/day 1 was 0.48-0.84 (point estimator 0.66) in control subjects and 0.54-0.72 (point estimator 0.64) in cirrhotic patients, respectively. 5An inverse correlation was seen between the results of the monoethylglycin-xilidid (MEGX)-test and the AUC of trapidil (single dose: r=−0.516, P=0.048; steady state: r=−0.548, P=0.042). 6Results of study I and study II indicate an autoinduction of trapidil metabolism after repeated oral doses. Although trapidil elimination is decreased in patients with liver cirrhosis (study II), the elimination half-life at steady state is relatively short (2.4 [±1.1 s.d.] h) and therefore should prevent cumulation of trapidil even in cirrhotic patients. [ABSTRACT FROM AUTHOR]

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]

Figures from the Editor's selected issue highlights 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/ You will really like this issue of the Br J Clin Pharmacology! In the third paper Gerd Mikus, from Heidelberg, Germany, describes a micro-dosed cocktail of three DOACs that can be used to identify drug-drug interactions. Stefan Weisshaar I et al i . from Vienna, Austria, are actively fighting this other epidemic and investigated the clinical effects of various dose ratios of morphine and naloxone in OUD patients. [Extracted from the article]

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Aims: Sewage treatment effluent with pharmaceutical residues is discharged into surface waters, raising societal concerns. The aim of this paper is to describe the Dutch chain approach on medicinal residues in water that has been implemented by the Dutch government. We show how stakeholders from both the health and water sectors have got actively involved. Within this chain approach, source measures as well as end‐of‐pipe measures are identified and, where feasible and effective, implemented. Methods: Descriptive paper on the Dutch chain approach. Results: Getting the water and health care sectors to talk with each other instead of about each other was the key accomplishment. Comprehension of each other's viewpoints, terminology, policy goals and span of control, was pivotal in setting shared goals, creating perspective about possible measures and actually taking (joint) action. Together, stakeholders agreed to act within their own possibilities, without pointing at others, and to focus on pragmatic measures. In this article, we provide examples of measures taken, pilot projects performed, and of measures that were not implemented. Besides this, we discuss the most important barriers encountered during this process and how they were overcome. Conclusion: The issue of pharmaceuticals in the environment is a wicked problem, which makes it necessary to work together with many stakeholders on possible solutions, avoiding paralysis by complexity. Most importantly, stakeholders need to invest in mutual understanding, keep an open communication, and feel invited to bring in solutions for their part of the chain. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Therapeutic drug monitoring for astronauts faces limitations in conventional blood sampling and sample management onboard the international space station. Here, we explore the feasibility of dried blood spot (DBS) collection during parabolic flights (PF) to overcome these constraints.We assessed the feasibility of blood deposition on blotting paper for preanalytical aspects in a PF using synthetic blood. Subsequently, DBS sampling validation was carried out in another PF campaign. Twenty volunteers participated in a pharmacokinetic study on caffeine and its metabolite, paraxanthine, conducted during parabolic flights. After >18 h caffeine washout, coffee (115 mg), tea (30 mg) or dark chocolate (11 mg) were ingested by the participants. DBS samples were collected at baseline, during weightlessness and post‐flight. Caffeine and paraxanthine were analysed using liquid chromatography–tandem mass spectrometry (LC‐MS/MS). Genotyping for cytochrome P450‐1A2 (CYP1A2) was performed and a metabolic ratio by area under the curve for caffeine and paraxanthine (AUCPAX/AUCCAF) for CYP1A2 was determined. A user experience survey was also conducted.Full in‐flight pharmacokinetic study was feasible in seventeen volunteers with three unable to perform the sampling due to motion sickness. Nineteen participants (twelve males and seven females) completed pharmacokinetic profiles, with repeated pharmacokinetic studies for six participants. CYP1A2 genotyping resulted in eight ultrarapid, eleven intermediate, and one poor metabolizer. Among the women, four were on oestrogen contraceptives, a known inhibitor of CYP1A2, and were considered as poor metabolizers. Expected differences in kinetic profiles, consistent with consumption habits, the ingested dose and the genotypic/phenotypic information, were observed. The mean caffeine AUC for coffee, tea and chocolate were 9419 ng.h.mL−1 (95% confidence interval [CI]: 6222–12 616, n = 10), 6917 ng.h.mL−1 (95% CI: 2729–11 105), n = 7) and 3039 ng.h.mL−1 (95% CI: 1614–4142, n = 12), respectively. The mean paraxanthine AUC were 10 566 ng.h.mL−1 (95% CI: 6242–14 890, n = 10), 4011 ng.h.mL−1 (95% CI: 2305–5716, n = 7) and 3638 ng.h.mL−1 (95% CI: 1589–40 859, n = 12), respectively. The mean metabolic ratio in oestrogen‐treated women was 0.53 (95% CI: 0.35–0.71) compared to 1.19 (95% CI: 0.99–1.33) in others. The mean metabolic ratio was 1.02 (95% CI: 0.81–1.23, n = 15) on the ground and 1.10 (95% CI: 0.70–1.41, n = 13) during the parabolic flights, with no significant difference observed between the two conditions. Overall participants were satisfied with the usability of the method.DBS collection was safe, stable, feasible and well accepted in weightlessness. This method would offer valuable insights into human metabolism adaptation during long‐term spaceflight, addressing space pharmacology challenges. [ABSTRACT FROM AUTHOR]

Generating and translating high‐quality evidence is integral to providing safe and effective medication management for residents of aged care homes. Residents are often under‐represented in trials of medication effectiveness and safety. This paper reviews opportunities and challenges for generating and translating evidence for safe and effective medication management in aged care homes. There are an increasing number of randomized controlled trials (RCTs) being conducted in aged care homes. Observational studies can also help address the evidence‐practice gap arising from underrepresentation of residents in RCTs. Stepped‐wedge and helix counterbalanced designs may help overcome limitations of traditional RCTs for evaluating medication management interventions in the aged care setting. Strategies for generating evidence include building effective partnerships with aged care homes and organizations, using novel trial designs, leveraging existing data and knowledge sharing through international platforms. Strategies for translating evidence include using quality indicators for audit and feedback, provision of education and training, engaging internal and external stakeholders, and development of local action plans and guideline implementation tools. There is an emerging interest in the role of knowledge brokers to facilitate knowledge translation. Future directions for generating and translating evidence include strengthening international research collaboration, industry partnerships, standardizing aged care home data to support national and international comparisons, and optimizing the use of technology. Initiatives may include improving access to routinely collected administrative health and medication data for conducting high‐quality observational studies. Future studies should assess outcomes prioritized by residents to ensure that medication management strategies are tailored to their needs. [ABSTRACT FROM AUTHOR]

Aims: Previous systematic reviews suggest that deprescribing may improve survival, particularly in frail older people. Evidence is rapidly accumulating, suggesting a need for an updated review of the literature. Methods: We updated a 2016 systematic review and meta‐analysis to include studies published from inception to 26 April 2024 from specified databases. Studies in which older people had at least one medication deprescribed were included and grouped by study designs and targeted medications. The risk of bias was assessed using the Cochrane tool and the Newcastle‐Ottawa tool. Odds ratios (OR) or mean differences were calculated as the effect measures using either the Mantel–Haenszel or generic inverse‐variance method with fixed‐ or random‐effects meta‐analyses. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, physical health, cognitive function, quality of life and effect on medication regimen. Subgroup analyses were performed based on age and intervention types. Results: A total of 259 studies (reported in 286 papers) were included in this updated review. Deprescribing polypharmacy did not result in a significant reduction in mortality in both randomized (OR 0.96, 95% confidence interval [CI] 0.84–1.09) and non‐randomized studies (OR 0.70, 95% CI 0.36–1.38). Further subgroup analyses of randomized studies on deprescribing polypharmacy demonstrated a significant reduction in mortality in the young old (aged 65–79) (OR 0.71, 95% CI 0.51–0.99) and when patient‐specific interventions were applied (OR 0.79, 95% CI 0.63–0.99). Conclusions: Deprescribing can be achieved with potentially important benefits in terms of improved survival, particularly when patient‐specific interventions are applied and initiated early in the young old. [ABSTRACT FROM AUTHOR]

In comparison to the efforts required to bring a new drug or formulation to the clinic, bestowing a name on a medicine is relatively simple. However, if the name we choose causes confusion—by making its contents ambiguous or if it is too alike another drug—it can precipitate clinical errors. This prompted the World Health Organization to set up the International Nonproprietary Naming Committee in the 1970s to select unambiguous names for drugs. Unfortunately, multidrug products—which are becoming increasingly popular—do not fall under the remit of conventional International Non‐proprietary Nomenclature. We have identified 26 combination formulations that have been historically named with the co‐drug format in the United Kingdom. Most of them have also been prescribed in the United Kingdom in the past year, and although several of them are not prescribed very often, 11 were prescribed more than 2000 times. In this paper, we have explored the literature to identify prescribing errors with co‐drug products and found several idiosyncrasies that have caused drug errors in the past. We advocate for a standard nomenclature (state the international nonproprietary name [INN] of each component followed by dose information in the x + y format) for these products on the box and in prescribing resources. We hope that this will enhance clarity and safety during prescribing and administration, particularly for high‐volume drugs like paracetamol + codeine (co‐codamol), amoxicillin + clavulanic acid (co‐amoxiclav) and trimethoprim + sulfamethoxazole (co‐trimoxazole). [ABSTRACT FROM AUTHOR]

Aims Researchers in clinical and pharmacoepidemiology fields have adopted information technology (IT) and electronic data capture, but these remain underused despite the benefits. This review discusses electronic case report forms and electronic data capture, specifically within pharmacoepidemiology and clinical research. Methods The review used PubMed and the Institute of Electrical and Electronic Engineers library. Search terms used were agreed by the authors and documented. PubMed is medical and health based, whereas Institute of Electrical and Electronic Engineers is technology based. The review focuses on electronic case report forms and electronic data capture, but briefly considers other relevant topics; consent, ethics and security. Results There were 1126 papers found using the search terms. Manual filtering and reviewing of abstracts further condensed this number to 136 relevant manuscripts. The papers were further categorized: 17 contained study data; 40 observational data; 27 anecdotal data; 47 covering methodology or design of systems; one case study; one literature review; two feasibility studies; and one cost analysis. Conclusion Electronic case report forms, electronic data capture and IT in general are viewed with enthusiasm and are seen as a cost-effective means of improving research efficiency, educating participants and improving trial recruitment, provided concerns about how data will be protected from misuse can be addressed. Clear operational guidelines and best practises are key for healthcare providers, and researchers adopting IT, and further work is needed on improving integration of new technologies with current systems. A robust method of evaluation for technical innovation is required. [ABSTRACT FROM AUTHOR]

Chemodenervation with botulinum neurotoxin type A (BoNTA) is the preferred method for focal spasticity management among various treatment options. While BoNTA injection is considered safe, its widespread use and increasing evidence raise safety concerns. In this paper, we present a patient with central pontine myelinolysis, a rare disease, who developed acute respiratory distress syndrome on the third day after BoNTA application to the spastic gastrocnemius muscle group and required intubation in the intensive care unit due to this complication. To our knowledge, this is the first case reported in the literature to develop an acute pulmonary complication after BoNTA injection into spastic lower extremity muscles. [ABSTRACT FROM AUTHOR]

Aim: Pharmacokinetics have historically been assessed using drug concentration data obtained via blood draws and bench‐top analysis. The cumbersome nature of these typically constrains studies to at most a dozen concentration measurements per dosing event. This, in turn, limits our statistical power in the detection of hours‐scale, time‐varying physiological processes. Given the recent advent of in vivo electrochemical aptamer‐based (EAB) sensors, however, we can now obtain hundreds of concentration measurements per administration. Our aim in this paper was to assess the ability of these time‐dense datasets to describe time‐varying pharmacokinetic models with good statistical significance. Methods: We used seconds‐resolved measurements of plasma tobramycin concentrations in rats to statistically compare traditional one‐ and two‐compartmental pharmacokinetic models to new models in which the proportional relationship between a drug's plasma concentration and its elimination rate varies in response to changing kidney function. Results: We found that a modified one‐compartment model in which the proportionality between the plasma concentration of tobramycin and its elimination rate falls reciprocally with time either meets or is preferred over the standard two‐compartment pharmacokinetic model for half of the datasets characterized. When we reduced the impact of the drug's rapid distribution phase on the model, this one‐compartment, time‐varying model was statistically preferred over the standard one‐compartment model for 80% of our datasets. Conclusions: Our results highlight both the impact that simple physiological changes (such as varying kidney function) can have on drug pharmacokinetics and the ability of high‐time resolution EAB sensor measurements to identify such impacts. [ABSTRACT FROM AUTHOR]

Pharmacovigilance studies based on spontaneous reporting systems use disproportionality analysis methods to identify drug‐event combinations with higher‐than‐expected reporting. Enhanced reporting is deemed as a proxy for a detected signal and is used to generate drug safety hypotheses, which can then be tested in pharmacoepidemiologic studies or randomized controlled trials. Higher‐than‐expected reporting means that the reporting rate of a drug‐event combination of interest is disproportionately higher than the rate in a specific comparator or reference set. Currently, it is unclear which comparator is the most appropriate for use in pharmacovigilance. Moreover, it is also unclear how the selection of a comparator may affect the directionality of the various reporting and other biases. This paper reviews commonly used comparators chosen for signal detection studies (active comparator, class‐exclusion comparator, and full data reference set). We give an overview of the advantages and disadvantages of each method based on examples from the literature. We also touch upon the challenges related to the derivation of general recommendations for the selection of comparators when mining spontaneous reports for pharmacovigilance. [ABSTRACT FROM AUTHOR]

Evidence-based recommendations for haemodialysis in lithium-poisoned patients: Getting from where we are to where we want to be In the first paper, Vodovar et al performed a retrospective analysis of lithium-poisoned patients from a single ICU in Paris.[13] They derived a simple set of clinical criteria and suggest that these new criteria outperform the EXTRIP criteria. Similarly, Buckley retrospectively analysed patients from three local hospitals and performed a toxicokinetic evaluation to identify patients whose lithium concentrations were likely to remain elevated for a prolonged period of time.[14] Both groups address parameters (the peak serum lithium concentration, prolonged lithium elimination, and individual patient factors) that were recognized decades ago as likely markers of morbidity[15] and were evaluated and included in the EXTRIP recommendations.[11] Both Vodovar's and Buckley's papers demonstrate that the EXTRIP criteria correctly identified every patient who needed ECTR in their cohorts. [Extracted from the article]

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]

Opioid use disorder (OUD) and chronic pain are commonly co‐occurring disorders which can exacerbate each other. Sex/gender differences have been shown in aspects of the clinical course and biological underpinnings of both OUD and chronic pain. The purpose of this scoping review is to summarize literature which has addressed sex/gender differences in relation to the confluence of OUD and chronic pain. This review focused on peer‐reviewed journal articles with human subjects and addressing (a) opioid misuse, chronic opioid use or opioid use disorder (OUD), (b) chronic or persistent pain and (c) sex/gender differences in relation to OUD and/or chronic pain. Of the 146 papers identified by the search strategy, 30 met the criteria for inclusion. Charting focused on a priori themes of chronic pain, opioid misuse/OUD and sex/gender in sample, predictor and outcome variables, and key study findings. The majority of research identified was cross‐sectional in nature, and sex/gender differences and treatment effects were largely included as post‐hoc analyses. Together, the results of this early work align with higher prevalence for OUD in men/males and chronic pain in women/females, while adding critical information with respect to potential sex/gender differences in the development and treatment of their co‐occurrence across a range of biological and psychosocial factors. Findings underline the importance of considering sex and gender in the intersection of the development and treatment of OUD and chronic pain. [ABSTRACT FROM AUTHOR]

In solid organ transplantation (SOT), biologicals such as recombinant therapeutic proteins, monoclonal antibodies, fusion proteins and conjugates are increasingly used for immunosuppression, desensitization, ABO (blood group) incompatibility, antibody‐mediated rejections and atypical haemolytic uremic syndrome. In this paper, we review the medical evidence available for biologicals used in SOT and the potential for improvement by the application of therapeutic drug monitoring (TDM) and model‐informed precision dosing. Biologicals are used for off‐label indications within the field of SOT, building on the experience from their use on labelled indications. Dosing is currently mostly standard, and experience vs. effect and toxicity is limited. Pharmacokinetic characteristics of these large, partly also immunogenic molecules differ from those of traditional small molecules. Individualization by concentration measurements and modelling has mostly been proof‐of‐concept or feasibility studies that lack the power to provide evidence for improvement in clinical outcome. For some drugs such as alemtuzumab, eculizumab, rituximab, tocilizumab and belatacept, studies have demonstrated significant interindividual variability in pharmacokinetics. Variability in absorption from subcutaneous administration may increase interindividual variability. There is also an economic aspect of appropriate dosing that needs to be pursued. Available assays and models to refine interpretation are in place, but trials of adequate size to document the usefulness of TDM and MIPD are scarce. Collaboration within the TDM community seems mandatory to establish studies of sufficient strength to provide evidence for the use of biologicals that are currently used off‐label in SOT and furthermore to identify the settings where TDM may be beneficial. [ABSTRACT FROM AUTHOR]

Aims: The global older population is growing rapidly, and the rise in polypharmacy has increased potentially inappropriate medication (PIM) encounters. PIMs pose health risks, but detecting them automatically in large medical databases is complex. This review aimed to uncover PIM prevalence in individuals aged 65 years or older using health databases and emphasized the risk of underestimating PIM prevalence due to underutilization of detection tools. Methods: This study conducted a broad search on the Medline database to identify articles about the prevalence of PIMs in older adults using various databases. Articles published between January 2010 and June 2023 were included, and specific criteria were applied for study selection. Two literature reviews conducted before our study period were integrated to obtain a perspective from the 1990s to the present day. The selected papers were analysed for variables including database type, screening method, adaptations and PIM prevalence. The study categorized databases and original screening tools for clarity, examined adaptations and assessed concordance among different screening methods. Results: This study encompassed 48 manuscripts, covering 58 sample evaluations. The mean prevalence of PIMs within the general population aged over 65 years was 27.8%. Relevant heterogeneity emerged in both the utilized databases and the detection methods. Adaptation of original screening tools was observed in 86.2% (50/58) of cases. Half of the original screening tools used for assessing PIMs belonged to the simple category. About a third of the studies employed less than half of the original criteria after adaptation. Only three studies used over 75% of the original criteria and more than 50 criteria. Conclusions: This extensive review highlights PIM prevalence among the older adults, emphasizing method intricacies and the potential for underestimation due to data limitations and algorithm adjustments. The findings call for enhanced methodologies, transparent algorithms and a deeper understanding of intricate rules' impact on public health implications. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) infection frequently occurs after solid organ transplantation and is associated with an increased morbidity and mortality. Fortunately, the development of valganciclovir prophylaxis has lowered the incidence of CMV infection and its complications in immunosuppressed solid organ transplant recipients. However, breakthrough infections during valganciclovir prophylaxis and late CMV infection after cessation of valganciclovir prophylaxis still occur with the current prophylactic strategy. Additionally, valganciclovir resistance has emerged among CMV strains, which complicates the treatment of CMV infections. Furthermore, the use of valganciclovir is associated with myelotoxicity, which can lead to the premature withdrawal of prophylaxis. It is important to address these current issues in order to improve the standard care after solid organ transplantation. This paper will therefore discuss the clinical practice of valganciclovir prophylaxis, elaborate on its issues and suggest how to improve the current prophylactic strategy with a possible role for therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

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]

2022; 88 (12): 4985 - 4996. doi: 10.1111/bcp.15571 6 Aurich B, Apele-Freimane D, Banaschewski T, et al. c4c: Paediatric pharmacovigilance: methodological considerations in research and development of medicines for children - a c4c expert group white paper. At the same time almost half of these prescriptions are off-label, due to a historical lack of medicines specifically developed for children.1 For ethical, practical and economic reasons, academic and industry researchers were reluctant to study drugs in children. On average, half of all children in Europe take medicines, either for acute or chronic illness. [Extracted from the article]

Aims The objective of this review was to collect available data on the following: (i) adverse effects observed in humans from the intake of plant food supplements or botanical preparations; (ii) the misidentification of poisonous plants; and (iii) interactions between plant food supplements/botanicals and conventional drugs or nutrients. Methods PubMed/ MEDLINE and Embase were searched from database inception to June 2014, using the terms 'adverse effect/s', 'poisoning/s', 'plant food supplement/s', 'misidentification/s' and 'interaction/s' in combination with the relevant plant name. All papers were critically evaluated according to the World Health Organization Guidelines for causality assessment. Results Data were obtained for 66 plants that are common ingredients of plant food supplements; of the 492 papers selected, 402 (81.7%) dealt with adverse effects directly associated with the botanical and 89 (18.1%) concerned interactions with conventional drugs. Only one case was associated with misidentification. Adverse effects were reported for 39 of the 66 botanical substances searched. Of the total references, 86.6% were associated with 14 plants, including Glycine max/soybean (19.3%), Glycyrrhiza glabra/liquorice (12.2%), Camellia sinensis/green tea ( 8.7%) and Ginkgo biloba/gingko (8.5%). Conclusions Considering the length of time examined and the number of plants included in the review, it is remarkable that: (i) the adverse effects due to botanical ingredients were relatively infrequent, if assessed for causality; and (ii) the number of severe clinical reactions was very limited, but some fatal cases have been described. Data presented in this review were assessed for quality in order to make the results maximally useful for clinicians in identifying or excluding deleterious effects of botanicals. [ABSTRACT FROM AUTHOR]