Aim Prescribing of antidepressant and antipsychotic drugs in general populations has increased in the UK, but prescribing trends in people with type 2 diabetes (T2D) have not previously been investigated. The aim of this study was to describe time trends in annual prevalence of antidepressant and antipsychotic drug prescribing in adult patients with T2D. Methods Repeated annual cross-sectional analyses of a population-based diabetes registry, derived from primary and secondary care data in Scotland, from 2004 to 2021. For each cross-sectional calendar year time period, we calculated the prevalence of antidepressant and antipsychotic drug prescribing, overall and by sociodemographic characteristics and drug subtype. Results The number of patients with a T2D diagnosis in Scotland increased from 161,915 in 2004 to 309,288 in 2021. Prevalence of antidepressant and antipsychotic prescribing in patients with T2D increased markedly between 2004 and 2021 (from 20.0 per 100 person-years to 33.3 per 100 person-years and from 2.8 per 100 person-years to 4.7 per 100 person-years, respectively). We observed this pattern for all drug subtypes except for first-generation antipsychotics, prescribing of which remained largely stable. The degree of increase, as well as overall prevalence of prescribing, differed by age, sex, socioeconomic status, and subtype of drug class. Conclusion There has been a marked increase in the prevalence of antidepressant and antipsychotic prescribing in patients with T2D in Scotland. Further research should identify the reasons for this increase, including indication for use and the extent to which this reflects increases in incident prescribing rather than increased duration.

Phase 1 clinical drug trials critically depend on the participation of healthy volunteers to evaluate the safety and pharmacokinetics of new medicinal products. Current selection criteria and health definitions often overlook the unique health profiles of transgender and nonbinary individuals, potentially excluding them from participating in these essential early-stage studies. This review aims to identify and discuss current knowledge gaps and considerations regarding the inclusion of transgender and nonbinary participants in Phase 1 clinical drug trials. We highlight the need for research on how gender-affirming hormone therapy may affect drug pharmacokinetics and call for the development of inclusive biological reference ranges that account for the physiological effects of hormone therapies.

Clinical pharmacists are health care practitioners who have advanced education and training in comprehensive medication management. Clinical pharmacists participate in the management of specific medications or individual disease states and collaborate with other health care team. Despite the clinical pharmacist participate in healthcare team, there are several cases of challenge in the interprofessional relationship with other healthcare team especially related drug management. The role of clinical pharmacists could be improved by increasing interprofessional communication between doctors and clinical pharmacist in the healthcare system. Previous studies reported that physicians were comfortable with pharmacists detecting and preventing prescription errors, but were uncomfortable with them recommending drug therapy to patients. Acceptance of pharmacists' suggestions by prescribers is a necessary component of the evaluation of clinical pharmacy services.

The aims of the current review were to identify, in the context of people with acquired communication disorders: factors which influence medication adherence, current interventions targeting medication adherence, and how medication adherence is currently measured. This study was conducted and reported in accordance with both PRISMA and SWiM guidelines. Two authors independently screened the results of a literature search, assessed risk of bias, and extracted relevant data. Eight studies were identified for inclusion. Four of the studies presented information relating to current interventions which target medication adherence for people with acquired communication disorders. Four of the studies investigated factors which influence medication adherence for people with acquired communication disorders. Seven of these eight studies outlined methods used for measuring medication adherence. The results of this review indicate that patient related factors are most associated with medication non-adherence in a population with acquired communication disorders, followed by socio-economic factors and medication-related factors. Despite the recognised importance of medication adherence, no gold standard of assessment or intervention currently exist for this population. Half of the included studies replaced patients with communication difficulties with caregiver proxies, thus reducing opportunities for patients to participate meaningfully in research. The term “acquired communication disorders” encompasses a range of conditions with diverse aetiologies, presentations, and needs, and future research should be tailored to specific patient groups most at risk of medication non-adherence, namely those with aphasia and cognitive-communication impairments. Patients should be empowered to participate in future research to ensure the literature accurately represents their lived experience.

The rise of psychedelics in contemporary medicine has sparked interest in their potential therapeutic applications. While traditionally associated with countercultural movements and recreational use, recent research has shed light on the potential benefits of psychedelics in various mental health conditions. In this review, we explore the emerging role of psychedelics in the management of chronic pain and opioid use disorder (OUD), two critical areas in need of innovative treatment options. Pain control remains a significant clinical challenge, particularly for individuals with OUD and those who receive long-term opioid therapy (LTOT) who develop marked tolerance to opioid-induced analgesia. Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for these populations. Drawing from preclinical and human evidence, we highlight the potential of psychedelics to act on shared neurobiological substrates of chronic pain and opioid use disorder, potentially reversing pain- and opioid-induced neuroadaptations, such as central sensitization. We elaborate on the multifaceted dimensions of the pain experience (sensory, affective, and cognitive) and their intersections that overlap with opioid-related phenomena (opioid craving and withdrawal), hypothesizing how these processes can be modulated by psychedelics. After summarizing the available clinical research, we propose mechanistic insights and methodological considerations for the design of future translational studies and clinical trials, building on a shared clinical and neurobiological understanding of chronic pain and OUD. Our intention is to provide timely perspectives that accelerate the development and exploration of novel therapeutics for chronic pain and OUD amidst the escalating opioid crisis.

The C-reactive protein (CRP) can guide the antibiotic prescription for infectious diseases which are likely viral. We identified all patients, aged 15 years or older, being registered in the database between January, 1, 2000 and December, 31, 2019 and newly diagnosed with upper respiratory tract infections (URTIs), COPD- or asthma-related exacerbations. From the date of these diagnoses, patients were followed up until occurrence of antibiotic prescription (for these indications) up to December 31, 2019. The association between the prescription of CRP and the outcome was investigated using a nested case-control analysis. In a cohort of 469,684 patients being diagnosed for URTI (83%), COPD- (11%) and asthma (7%)-related exacerbations, 28688 (6.11%) were prescribed with antibiotics because of the aforementioned indications. Of note, 98% of cases were not tested with CRP. Those receiving antibiotics showed a greater propensity to be previously tested for CRP than related controls. Our findings indicate that most of the antibiotic prescriptions for the investigated conditions did not report prior evaluation of CRP values. Nevertheless, it seems that some GPs properly used CRP before deciding for an antibiotic therapy. Further information and incentives in using CRP test should be therefore sustained in primary care.

Caspofungin is an echinocandin antifungal commonly used as the first-line therapy for invasive candidiasis, salvage therapy for invasive aspergillosis. Pharmacokinetic variabilities and suboptimal exposure have been reported for caspofungin, increasing the risk of insufficient efficacy. We aimed to consolidate information from population pharmacokinetic studies, compare model performance, identify significant covariates affecting caspofungin’s PKs, evaluate probability of target attainment in different studies and assemble pharmacokinetic/pharmacodynamic target to address existing knowledge gaps that may warrant further investigation in future. We performed a systematic search strategy to review the PPK studies of caspofungin. Four databases were searched. We extracted information for the comparison of models, evaluation of the impact of covariates on clearance and apparent volume and the calculation of probability of target attainment under specific minimum inhibitory concentration. Thirteen studies were included. The simulation results showed that under labeled dose, pediatrics exhibited notably higher exposure than adults. Body size was the most identified covariate that affected both clearance and volume of distribution. For C. albicans and C. parapsilosis, none of the populations achieved a PTA of ≥ 90%. In contrast, for C. glabrata, 70% of the adult patients reached a PTA of ≥ 90%, while all pediatric patients achieved the same PTA level. At the recommended dosage, adults showed lower exposure to caspofungin compared to pediatrics. It is crucial to consider body size, liver function and serum albumin when determining caspofungin dosage regimens. Furthermore, further research is required to comprehensively understand the pharmacokinetics of caspofungin in pediatrics.

Aim: To examine and understand the work processes of AMS teams across two hospitals that use the same digital intervention, and to identify the challenges and enablers to effective AMS in each setting. Methods: Employing a contextual inquiry approach informed by the Systems Engineering Initiative for Patient Safety (SEIPS) model, observations and semi-structured interviews were conducted with AMS team members (n=15) in two Australian hospitals. Qualitative data analysis was conducted, mapping themes to the SEIPS framework. Results: Both hospitals utilised similar systems, however, they displayed variations in AMS processes, particularly in post-prescription review, interdepartmental AMS meetings, and the utilisation of digital tools. An antimicrobial dashboard was available at both hospitals but was utilised more at the hospital where the AMS team members were involved in the dashboard’s development, and there were user champions. At the hospital where the dashboard was utilised less, participants were unaware of key features, and interoperability issues were observed. Establishing strong relationships between the AMS team and prescribers emerged as key to effective AMS at both hospitals. However, organisational and cultural differences were found, with one hospital reporting insufficient support from executive leadership, increased prescriber autonomy, and resource constraints. Conclusion: Organisational and cultural elements, such as executive support, resource allocation, and interdepartmental relationships, played a crucial role in achieving AMS goals. System interoperability and user champions further promoted the adoption of digital tools, potentially improving AMS outcomes through increased user engagement and acceptance.

Many science and health profession graduates lack fundamental pharmacology knowledge and the ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond ‘know’ towards ‘know how to’. A concept-based approach will help educators prioritise and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities, and improve the application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified, unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts in Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realise these benefits, pharmacology educators must identify, unpack, and develop methods to teach and assess core concepts. Work to develop a concept inventories is ongoing, including the identification of student misconceptions of the core concepts and the creation of a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented.

Aim: To measure the prevalence of polypharmacy and describe the prescribing of potentially inappropriate medication (PIM) in older people with polypharmacy in primary care. Methods: A multi-country retrospective cohort study across six countries: Belgium, France, Germany, Italy, Spain, UK. We used anonymized longitudinal patient level information from general practice databases hosted by IQVIA. Patients ≥65 years were included. Polypharmacy was defined as having 5-9, and ≥10 distinct drug classes (ATC Level 3) prescribed during a 6-month period. PIM defined: opioids, antipsychotics, proton pump inhibitors (PPI), benzodiazepines (ATC Level 5). We included country experts on the health care context to interpret findings. Results: Age and gender distribution was similar across the six countries (mean age 75-76 years; 54-56% female). The prevalence of polypharmacy of 5-9 drugs was 22.8% (UK) to 58.3% (Germany); ≥10 drugs from 11.3% (UK) to 28.5% (Germany). In the polypharmacy population prescribed ≥5 drugs, opioid prescribing ranged from 11.5% (France) to 27.5% (Spain). Prescribing of PPI was highest with almost half of patients receiving a PPI, 42.3% (Germany) to 65.5% (Spain). Benzodiazepine prescribing showed a marked variation between countries, 2.7% (UK) to 34.9% (Spain). The health care context information explained possible underreporting for PIM. Conclusion: We have found a high prevalence of polypharmacy with more than half of the older population being prescribed ≥5 drugs in four of the six countries. Whilst polypharmacy may be appropriate in many patients, worrying high usage of PIM (PPIs and benzodiazepines) supports current efforts to improve polypharmacy management across Europe.

Infants bear a significant malaria burden but are usually excluded from participating in early dose optimisation studies that inform dosing regimens of antimalarial therapy. Unlike older children, infants’ exclusion from early-phase trials has resulted in limited evidence to guide accurate dosing of antimalarial treatment for uncomplicated malaria or malaria preventive treatment in this vulnerable population. Subsequently, doses used in infants are often extrapolated from older children or adults, with the potential for under or overdosing. Population pharmacokinetic-pharmacodynamic (PK-PD) modelling, a quantitative methodology that applies mathematical and statistical techniques, can aid the design of clinical studies in infants that collect sparse pharmacokinetic data as well as support the analysis of such data to derive optimised antimalarial dosing in this complex and at-risk yet understudied subpopulation. In this review, we reflect on what PK-PD modelling can do in programmatic settings of most malaria-endemic areas and how it can be used to inform antimalarial dose optimisation for preventive and curative treatment of uncomplicated malaria in infants. We outline key developmental physiological changes that affect drug exposure in early life, the challenges of conducting dose optimisation studies in infants, and examples of how PK-PD modelling has previously informed antimalarial dose optimisation in this subgroup. Additionally, we have discussed the limitations and gaps of PK-PD modelling when used for dose optimisation in infants and best practices for using population PK-PD methods in this subgroup.

Pain and opioid use disorder (OUD) are inextricably linked, as the former can be a risk factor for the development of the latter, and over a third of persons with OUD suffer concomitant chronic pain. Assessing pain among people with OUD is challenging, be-cause ongoing opioid use brings changes in pain responses and most pain assess-ment tools have not been validated for this population. In this narrative review, we discuss the fundamentals of pain assessment for populations with OUD. First, we de-scribe biological, psychological, and social aspects of the pain experience among people with OUD, as well as how opioid-related phenomena and healthcare dispari-ties in this population may contribute to the pain experience. Second, we review meth-ods to assess pain including: (1) traditional self-reported methods, such visual analog scales, and structured questionnaires; (2) behavioral observations and physiological indicators; (3) and laboratory-based approaches, such as functional brain imaging, electroencephalography, and quantitative sensory testing. These methods are consid-ered from a perspective that encompasses both pain and OUD. Finally, we discuss strategies for improving pain assessment in persons with OUD and implications for future research, including educational strategies for multidisciplinary teams. Substan-tial gaps persist in our knowledge, particularly regarding the applicability of current pain assessment methods to persons with OUD, as well as the generalizability of the existing results from adjacent populations. As research linking pain and OUD evolves, considering the needs of diverse populations with complex psychosocial back-grounds, we will be better equipped to reduce these gaps.

Aims. The exposure-response relationship of bevacizumab may be confounded by various factors, i.e. baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response. This work aimed at investigating the exposure-response relationships of bevacizumab in mCRC patients while mitigating potential sources of bias. Methods. Bevacizumab pharmacokinetics was described using target-mediated drug disposition (TMDD) modeling. The relationships between target kinetics, and progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both potential biases due to prognostic-driven and response-driven of the concentration-effect relationship were mitigated. These models were used to evaluate the effect of increased antigen target levels and clearance, as well as intensified dosing regimen, on survival. Results. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were: baseline target levels (R0=8.4 nM), steady-state dissociation constant (KSS=10 nM) and antibody-target complexes elimination constant (kint=0.52 day-1). Distribution of R0 was significantly associated with an increased baseline CEA and circulating VEGF levels, and the presence of extra-hepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increased R0 or CL values led to decreased bevacizumab unbound concentrations, increased R levels, and shortened PFS and OS, whereas increasing bevacizumab dose led to decreased R and longer survival. Conclusion. This study is the first to show the relationship between bevacizumab concentrations, target involvement and clinical efficacy by mitigating potential sources of bias. Most of target amount may be tumoral in mCRC. A more in-depth description of this relationship should be made in future studies.

Aim The reference nutrient intake for vitamin D in people aged ≥4 years is 10 μg/day (400 IU/day) in the UK, but the recommended daily allowance is 15 μg/day (600 IU/day) for people aged 1-70 years in the US. Here, we aim to compare the 25-hydroxyvitamin D3 (25(OH)D3) serum concentration profiles between the two doses. Methods With adult trial data, we constructed a physiologically based pharmacokinetics (PBPK) model of serum concentrations of vitamin D3 and 25(OH)D3 using nonlinear mixed effects (NLME) modelling. We used this model to forecast the mean, 5% and 95% percentiles for serum 25(OH)D3 concentrations. Results Our final model uses bodyweight to adjust volume of each compartment and maximum clearance of 25(OH)D. No other covariate was identified. The model accurately predicted data from trials of a broad range of dose regimens. We simulated subjects of the average UK male and female weights with baseline 25(OH)D < 25 nmol/L. Simulation suggests circulating 25(OH)D concentrations in >5% of men and women taking 10 μg/day for a year might fail to reach 50 nmol/L, while those on 15 μg/day were predicted to attain this threshold. Conclusion The two doses generate significant difference in serum 25(OH)D3 concentrations. This needs to be considered for choosing the right dose for the public health guideline.

Aim: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large inter-individual variability was found in its pharmacokinetics, and how to handle a delayed or missed dose of INH remains unclear. This study aimed to develop a population pharmacokinetics (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for non-adherent patients. Methods: A nonlinear mixed-effects modeling was used to analyze the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. A two-compartment model well described the PPK of INH. Results: N-acetyltransferase 2 (NAT2) genotype and body weight were identified as significant factors on INH PK. Monte Carlo simulations determined optimal dosage regimens for patients with different NAT2 genotype and body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. On delaying a INH dose exceed 12 h, only need to take the next single dose normally. Conclusion: PPK modeling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.

Aims: There is no specific guidance on optimal clozapine plasma concentrations in older people. This study aimed to test the hypothesis that therapeutic plasma clozapine concentrations would be lower in patients with an onset of psychosis after 60 years, compared to those with an earlier onset of schizophrenia (EOS) and to investigate the relationship between pharmacokinetic indices and side effects. Methods: Data were extracted from anonymised healthcare records for clozapine treated patients aged over 55 years. Median plasma clozapine and norclozapine concentrations (Cclozapine, Cnorclozapine) were compared across diagnostic groups. Mixed-effects models were used to investigate the relationship between pharmacokinetic biomarkers and side effects. Results: Of the 481 patients (4519 samples, median 6 per person), 430 (89.4%) were diagnosed with EOS. Cclozapine and Cnorclozapine in those with Parkinson’s disease psychosis (0.17mgL-1, 0.08mgL-1) were lower than those with EOS (0.41mgL-1, 0.19mgL-1), dementia-related psychosis (0.40mgL-1, 0.24mgL-1) and very late-onset schizophrenia-like psychosis (0.42mgL-1, 0.17mgL-1). Cclozapine was associated with higher corrected QT interval (QTc), whilst Cclozapine and Cnorclozapine were associated with higher neutrophil counts and body mass index, but not with clinical thresholds for neutropenia, obesity, QTc prolongation, or with sedation. Conclusions: Our findings suggest that, compared to EOS, therapeutic plasma clozapine concentrations are lower in Parkinson’s disease psychosis but not in other forms of later onset psychosis. Interpretation was limited by the relatively young age of the sample and the small number of samples associated with side effects. Prospective studies are needed to further explore optimal dosing specifically in older people.

Cassia angustifolia is a species of a plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines. There are few described interactions between Senna and drugs, most of them related to electrolyte disturbances due to concomitant use with other laxatives or due to increased intestinal transit that may limit the absorption of drugs with low bioavailability. We present a case with supratherapeutic trough concentration of tacrolimus in a liver transplant patient after concomitant intake of tacrolimus and a herbal product based on Cassia angustifolia, suggesting a possible drug-plant interaction by means of P-glycoprotein. We observe an increase in their plasma concentration 2.8-fold and the AUC 2.1-fold.

Aims: To compare the outcomes of real-world Japanese patients with nonvalvular atrial fibrillation who are ineligible for phase III trials of direct oral anticoagulants with those of eligible patients. Methods: In retrospective cohort design, consecutively registered patients with nonvalvular atrial fibrillation who had taken warfarin were followed up and assessed eligibility of patients for phase III trials of direct oral anticoagulants. The effects of the ineligibility of patients on outcomes were estimated using Cox proportional hazards models to calculate the hazard ratio (HR) and 95% confidence interval. Results: We registered 7826 Japanese patients with nonvalvular atrial fibrillation from 71 hospitals. Nearly half (48.2%, n=3772) of these patients were ineligible for phase III trials of direct oral anticoagulants, mainly because of low CHADS2 scores (26.4%), renal dysfunction (9.5%), anemia (6.4%), and chronic treatment with nonsteroidal anti-inflammatories (4.0%). After excluding patients with a CHADS2 score <2 (n=2064, 26.4%) from total ineligible patients, the remaining ineligible patients (n=1708) exhibited significantly greater risks of major bleeding (unadjusted hazard ratio 2.00, 95% confidence interval 1.63–2.44, p<0.0001), stroke/systemic embolism (unadjusted hazard ratio 1.53, 95% confidence interval 1.17–1.98, p=0.0016), and all-cause mortality (unadjusted hazard ratio 2.84, 95% confidence interval 2.36–3.43, p<0.0001) compared to the eligible patients. Conclusions: The benefits and risks of direct oral anticoagulants suggested by phase III trials may not necessarily apply to patients ineligible for Phase III trials. This gap between evidence and practice is an issue in the real-world safety and efficacy of anticoagulants.