Background Voriconazole (VCZ) is a first-line treatment drug for invasive fungal disease, with narrow therapeutic window and significant inter-individual variability. VCZ is primarily metabolized by liver, which declines with age. For elderly patients, physiological and pathological factors lead to more pronounced fluctuations in VCZ plasma concentrations. Thus, it is crucial to establish a model that accurately predicts VCZ plasma concentration in elderly patients. Methods A retrospective study was performed incorporating 32 variables, including population pharmacokinetics (PPK) parameters derived from the PPK model. Recursive Feature Elimination with Cross-Validation was used for feature selection. Multiple algorithms were selected and combined into an ensemble model, and the model was interpreted by Shapley Additive exPlanations. Results The predictive performance of machine learning was greatly improved after inclusion of PPK parameters. The composition of XGBoost, RF, and CatBoost (1:1:8) with the highest R2 (0.828) was determined as the final ensemble model. Feature selection greatly simplified the model from 31 variables to 9 variables without compromising its performance. The R2, mean square error, mean absolute error, and accuracy (± 30%) of external validation were 0.633, 1.094, 2.286, and 71.05%, respectively. Conclusions Our study is the first to include PPK parameters as new factors for machine learning modeling to predict VCZ plasma concentrations in elderly patients. The model underwent optimization through feature selection. Our model provides a reference for individualized dosing of VCZ in clinical practice, enhancing the efficacy and safety of VCZ treatment in elderly patients. Keywords: voriconazole, elderly patients, machine learning, population pharmacokinetics, precision medicine

Introduction: Poor intra-operative blood pressure is a risk factor for kidney, heart, and cognitive post-operative complications. Literature suggests that use of low-dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic/pharmacodynamics (PK/PD) model of NOR effect on mean arterial pressure (mAP). Methods: From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intra-operative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared two models for NOR PD on mAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex. Results: We included 29 patients (age 52[46-64] years, 69% female). NOR median time to peak effect on mAP was 74[53-94] seconds. After bolus administration, mAP increased by 24% [15 - 31]. A 3-comparments model best captured NOR PK. NOR PD effect on mAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters. Conclusions: We developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on mAP over time, which could serve for target-controlled infusion. Study registration: ClinicalTrials.gov (NCT03454204)

Aim: Medication non-adherence is a global health problem affecting patients with numerous medical conditions. Training healthcare professionals (HCPs) on managing the challenging issue of medication non-adherence requires an evidence-based approach. Therefore, we aimed to describe the perspectives and experiences of adherence experts on educating HCPs about medication adherence in order to guide the content and delivery of medication adherence education to HCPs. Methods: Semi-structured interviews were conducted online, face-to-face, and via phone. Interviews were video or audio recorded and professionally transcribed. Data was coded line by line into the preliminary coding framework and analysed using inductive thematic analysis. Results: Fifteen adherence experts were interviewed between May 2022 and March 2023. Five major themes with subthemes were identified: enhancing awareness among HCPs, seeing life through the patient’s lens, communicating to build empathy and rapport, having a structured approach to address individual patient behaviours, and delivering enriching and targeted training. Conclusion: Adherence experts emphasised the impact HCPs can play by regularly addressing the pervasive issue of adherence in their clinical setting. HCPs can elicit behaviour change by understanding the patient’s perspective, the complexity of adherence, and communicating effectively. Structured approaches include using tools, frameworks, and communication methods. Continuous training that is clinically relevant and builds on existing professional expertise is required to overcome HCPs’ own barriers to behaviour change.The findings of this study guide the content and delivery of medication adherence education and training to HCPs.

Background: The South Korean government implemented the Narcotics Information Management System (NIMS) on 18 May 2018 to manage benzodiazepine receptor agonists (BzRAs) and narcotics effectively and establish a reporting mechanism for these drugs. This study assessed the effects of NIMS on inappropriate use of BzRAs. Methods: Using National Patient Sample data from 2016 to 2020, we analysed adult outpatients who were prescribed oral BzRAs. We conducted a time series and segmented regression analysis using selected indicators to analyse the monthly variations related to the inappropriate use of these medications. Results: The study revealed no significant changes in the indicators of inappropriate BzRA use following the NIMS implementation. Contrary to expectations, there was a significant increase in the proportion of patients exceeding Defined Daily Dose (DDD) and in those receiving concurrent prescriptions of multiple BzRAs, following the implementation of NIMS. The immediate impact of the COVID-19 pandemic was an increase in DDD exceedance; however, overall, this did not significantly affect BzRA use. Conclusion: The introduction of NIMS did not significantly enhance the management of BzRA misuse. Additional measures, including continuous monitoring, system improvements, and comprehensive education for prescribers and patients, are recommended to ensure the appropriate use of psychotropic medications.

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.

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.

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.

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: 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.

AIM Levetiracetam is a widely used anti-epileptic in the critical care setting that is almost exclusively (>90%) renally excreted. A significant number of critically unwell patients develop renal failure requiring haemofiltration. This paper investigates the pharmacokinetics of levetiracetam in such patients and the implications on dosing strategies. METHODS A systematic review of the available literature from 2000 was conducted. 7 articles were identified for inclusion from 54 records. A novel hybrid model was used to evaluate the quality of pharmacokinetic and haemofiltration data. Simulations were performed using pooled pharmacokinetic data to evaluate various dosing strategies. RESULTS Total clearance was 3.49 – 4.63L/hr (mean 3.55, S.D. 0.52). Elimination half-life was 5.66 – 12.88 hours (mean 9.41, S.D. 2.86). Volume of distribution was 0.45 – 0.73 L/kg. Levetiracetam clearance from CRRT was 52 – 73% (mean 54.7%, S.D. 13.5). At 72 hours, a significant proportion of simulated patients who received the recommended dose of levetiracetam demonstrated sub-therapeutic drug concentrations. Conversely, the majority who received a standard loading dose (60mg/kg) and twice daily doses in excess of 750mg demonstrated more consistent therapeutic drug concentrations. CONCLUSION Levetiracetam clearance in haemofiltration is similar to healthy adults with normal renal function. The current recommendation to dose as in CKD Stage 3b is likely to result in sub-therapeutic drug concentrations in a high number of patients. A twice daily dosing of 500 – 1,000 mg with an initial loading dose of 60mg/kg should be considered in such patients alongside therapeutic drug monitoring.

Shiga toxin-producing Escherichia coli-associated hemolytic uremic syndrome (STEC-HUS) is considered a toxemic disorder in which early intervention with neutralizing antibodies may have therapeutic benefits. INM004, composed of F(ab’)2 fragments from equine immunoglobulins, neutralizes Stx1/Stx2, potentially preventing the onset of HUS. A single-center, randomized, Phase 1, single-blind, placebo-controlled clinical trial to evaluate INM004 safety, tolerance, and pharmacokinetics (PK) in healthy adult volunteers, was conducted; In Stage I, eight subjects were divided in two cohorts (n=4) to receive a single INM004 dose of 2 or 4 mg.kg-1, or placebo (INM004:placebo rate 3:1). In Stage II six subjects received either three INM004 doses of 4 mg.kg-1 repeated every 24 h, or placebo (INM004:placebo rate of 5:1). Hospital discharged was 24 hours after the last infusion. INM004 was quantified by ELISA in serum samples obtained at predefined times. Safety and tolerability were assessed in both Stages by monitoring adverse events (AEs), laboratory test values, and vital signs. Eight subjects (57.1%) experienced treatment-emergent AEs (TEAEs), that resolved within 24 hours without requiring changes in treatment or additional intervention. No serious AEs were reported. Most TEAEs were of mild or moderate intensity, and four were possibly drug-related. Peak concentrations (Cmax) of INM004 were 45.1 µg.mL-1 and 77.7 µg.mL-1 for different doses, within two hours after infusion. The serum concentration declined in a biphasic manner (t1/2 range 30.7-52.9 hours). Systemic exposures showed accumulation in the repeated dose regimen (Cmax Day1 85.7 vs.149 µg.mL-1 Day3). These results supporting progression into the phase 2 trial in children with HUS

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may be associated with long-term health problems termed Long COVID or post COVID-19 syndrome. Symptoms can include fatigue, cognitive dysfunction, pain, anxiety, depression and sleep disturbances. There are few treatments available. Cannabis-based medicinal products (CBMPs) may reduce some of the common symptoms associated with Long COVID as they are known to ameliorate these symptoms occurring in other conditions. We conducted a single arm open label feasibility trial of the safety and tolerability of a full spectrum cannabidiol (CBD)-dominant CBMP for treating the symptoms of Long COVID. The treatment phase ran for a total of 21 weeks, followed by ~3 weeks without the study drug. Participants received up to 3 mL of MediCabilis 5% CBD Oil (50 mg CBD/mL, <2 mg THC/mL) per day orally. We recruited 12 (1 male, 11 female) individuals diagnosed with Long COVID into the trial. Monthly patient reported outcome measures (PROMs) of common symptoms and daily self-report of symptoms were collected via a smartphone app. Key measures of heart rate, activity, sleep, and oxygen saturation were assessed using wearable technology. All patients adhered to the treatment protocol for the duration of the study and there were no serious adverse events. Response rates for the research assessments were high with over 90% completion of PROMs and daily self-report. CBD-dominant CBMPs are safe and well tolerated in individuals diagnosed with Long COVID. Future work with larger samples and incorporating a control group should test the efficacy of this treatment.