British journal of clinical pharmacology最新文献

Aim: Appropriate drug exposure is as crucial as proper selection and timely antibiotic administration in sepsis treatment. However, evidence is lacking regarding the current dosing regimen to achieve pharmacodynamic targets. This study aimed to describe ceftriaxone pharmacokinetic (PK) parameters and establish optimal dosing regimens for sepsis patients.

Methods: This study investigated the pharmacokinetics of ceftriaxone in sepsis patients receiving ceftriaxone 2 g every 12 or 24 h. Blood samples (11-14 samples per patient) were collected within the first 24 h post-administration. PK parameters were estimated from unbound plasma concentrations using a nonlinear mixed-effects modelling approach (NONMEM® software). Monte Carlo simulations were conducted to evaluate the probability of target attainment of standard and high-dose ceftriaxone at various minimum inhibitory concentrations (MICs).

Results: Population PK analysis of 238 concentration-time data points from 20 patients revealed that a two-compartment model best described ceftriaxone PK. Glomerular filtration rate (GFR), serum albumin, and body weight significantly affected clearance, volume of distribution, and intercompartmental clearance, respectively. Simulation demonstrated that standard dose of 2 g every 24 h was adequate for pathogens with MIC ≤1 mg L^-1. At higher MIC values, target attainment decreased, particularly in with GFR > 130 mL·min^-1, with twice-daily dosing yielding higher exposures.

Conclusion: Standard ceftriaxone (2 g intravenous q 24 h, 30-min infusion) provided adequate target attainment at low MICs in this exploratory study of suspected sepsis. PTA decreased with higher MICs and higher renal function, with higher dose regimens showing numerically greater exposures. These findings may help guide future studies on dosing optimization.

Aim: Fluorescence-guided surgery enhances intraoperative visualization of anatomical structures. Nizaracianine is a near-infrared fluorescent agent that is exclusively renally cleared in animal models. It enables real-time ureteral imaging and identification, potentially reduces risk of injury and facilitates assessment before surgical closure. While a single dose has shown to be safe, repeated administration may be necessary during prolonged abdominopelvic procedures.

Methods: This Phase 1 study evaluated the safety, pharmacokinetics and fluorescence properties of repeated nizaracianine dosing in healthy volunteers. Participants received three doses at 0, 1 and 2 h across four dose cohorts: 3 × 0.5, 3 × 1.0, 3 × 2.5 and 3 × 5.0 mg. Safety assessments included vital signs, electrocardiography and laboratory testing. Plasma and urine samples were collected to determine pharmacokinetics. A Foley catheter was used for urine collection and measurement of fluorescence intensity over time.

Results: Twenty-one participants were included in the final analysis. Thirty-six adverse events were reported, mostly related to catheter placement. Nine events were possibly related to nizaracianine. In all cohorts, geometric means of C_{Max Plasma} (61.83, 122.9, 249.2 and 625.7), AUC_all (137.0, 276.9, 694.9 and 1835) and half-life (1.53, 1.52, 1.74 and 1.82) increased, suggesting dose proportionality. Cumulative renal clearance was 65%, indicating possible non-renal clearance pathways. Fluorescence signals were observed in all cohorts within 5 min of administration, persisting up to 8 h after the first dose.

Conclusion: Repeated intravenous doses of nizaracianine were well tolerated. PK suggests dose proportionality for C_max, AUC (area under the curve of the plasma concentration over time) and half-life, and fluorescence imaging of urine was possible from 5 min up until 8 h after initial dose.

The European Union Health Technology Regulation 2021/2282 (HTAR) introduces joint assessment of health technologies (including medicinal products and medical devices) across EU Member States. It was signed into law in 2021 and came into full force in January 2025. HTAR includes some core domains such as Joint Clinical Assessment (JCA), which refers to the relative effectiveness assessment of new technologies that have submitted a marketing authorization application to the EMA. It further includes Joint Scientific Consultation, which allows health technology developers to seek advice at an early stage in order to plan evidence generation in line with HTA needs. Such joint work will feed into respective national decision-making processes. While a JCA report will arguably fit directly into appraisal processes based on an added benefit framework, countries performing cost-effectiveness appraisal will be expected to incorporate a JCA into their value frameworks. In assessing the value of a new technology, however, HTA agencies face challenges stemming from the complexity of new technologies, a weakened evidence paradigm and a delay in access. The authors argue that HTAR can contribute towards solving some of the challenges through the reestablishment of evidence standards even for complex technologies, reduction of redundancies and a build-up of assessment capacity. Together with the suggested changes in the pharmaceutical regulation, HTAR may shorten the delay for late-access countries. HTAR is argued to be a major step towards a longer-term goal of equitable, efficient and high-quality healthcare in Europe, potentially leading towards the direction of one European HTA body.

Cyclosporine (CsA), an oral calcineurin inhibitor, is frequently used off-label in paediatric dermatology to manage severe inflammatory skin conditions rapidly. The current literature on this topic encompasses various sources, including systematic reviews, meta-analyses, case series, narrative reviews and clinical trials, with a focus on atopic dermatitis, chronic urticaria, drug reaction with eosinophilia and systemic symptoms (DReSS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), reactive infectious mucocutaneous eruption (RIME) and psoriasis. While some studies include adult data, they support the use of CsA as a viable treatment option in well-selected paediatric patients when accompanied by diligent monitoring. This review highlights common dosing strategies, typically weight-based and reports consistent rapid clinical improvement and steroid-sparing effects. Although adverse events may occur, they are generally reversible; however, careful monitoring is recommended.

Aims: CYP2B6 is a key enzyme involved in the metabolism of steroid hormones such as testosterone and estradiol. Common genetic CYP2B6 variants (*4, *5, *6, *9) are associated with reduced enzymatic activity and have been linked to increased breast cancer risk and poor prognosis. However, the impact of these genetic variants on testosterone and estradiol metabolism in humans is not understood. Therefore, this study aimed to investigate how these pharmacogenetic CYP2B6 variants affect metabolism of these steroid hormones in a human breast cancer model and how this may contribute to altered steroid hormone profiles in breast cancer.

Methods: T47D breast cancer cells were engineered to stably overexpress CYP2B6 wild type and the variants *4, *5, *6 and *9 using a retroviral pMOWS vector system. The metabolites 16α-/16β-hydroxytestosterone and 2-/4-hydroxyestradiol were analysed using HPLC-MS/MS after incubation of testosterone or estradiol with CYP2B6 and CYP1B1 supersomes and the modified T47D cells. Conversion of testosterone metabolites to oestrogens by aromatase was also tested.

Results: CYP2B6 supersomes predominantly formed 16β-hydroxytestosterone and 2-hydroxyestradiol, while CYP1B1 predominantly produced 16α-hydroxytestosterone and 4-hydroxyestradiol. CYP2B6*6 overexpression in T47D increased 16α-hydroxytestosterone formation, while *4 and 9 showed decreased metabolism compared to wild type. CYP2B6*5 produced reduced 16β-hydroxytestosterone levels. Aromatase converts 16α-metabolite to estriol and 16β-hydroxytestosterone to 16-epiestriol.

Conclusions: This study demonstrates that common CYP2B6 variants alter testosterone metabolism in a human breast cancer model, potentially disrupting steroid hormone balance and contributing to a tumour-promoting environment. These findings highlight the potential relevance of pharmacogenetic profiling in breast cancer risk assessment.

Aim: To develop and validate a multidimensional tool to assess adherence to warfarin therapy by Brazilian patients.

Methods: A Tool for Assessing Adherence to Warfarin Therapy (TAAW) was designed to encompass warfarin intake and other treatment-related aspects, including causal and effect items of adherence. The development process included: (i) construction of a concept map; (ii) elaboration of a preliminary version; (iii) expert assessment; (iv) semantic analysis through pre-testing with 30 participants; and (v) psychometric validation, including exploratory factor analysis, internal consistency, test-retest reliability and hypothesis testing.

Results: Of the 35 initially drafted items, 14 were discarded and 19 modified, resulting in a final version with 21 items distributed across three dimensions: warfarin intake (n = 10), self-care associated with warfarin use (n = 7) and health monitoring (n = 4). The TAAW tool demonstrated a unidimensional structure, excellent internal consistency (Cronbach's alpha = 0.98), high test-retest reliability (Intraclass Correlation Coefficient = 0.96) and strong correlation with the time in therapeutic range (Spearman's rho = 0.91), confirming its validity and reliability.

Conclusion: The validated TAAW is a robust instrument for assessing adherence to warfarin therapy in clinical and research settings. Its comprehensive approach allows for the identification of adherence patterns, enabling healthcare professionals to implement targeted interventions and optimize anticoagulation outcomes.

Sage, in collaboration with Biogen, submitted a new drug approval for zuranolone for postpartum depression (PPD) and major depressive disorder (MDD) in December 2022. In August 2023, the US Food and Drug Administration granted approval for PPD but denied approval for MDD. The approval process took only 7 months because it was given priority review and granted 'fast-track' designation, which is intended for drugs that fill unmet needs. This designation allows pharmaceutical companies to submit a smaller number of trials and limits evaluation to surrogate rather than clinically relevant outcomes. Indeed, policy shifts aiming to improve innovation and efficiency have lowered the threshold for evidence of benefit. In turn, this may skew the potential benefits versus potential harms for newly approved medicines in ways that are not in the public's best interest. We examine the clinical trial data submitted by the manufacturer for zuranolone and discuss how regulatory bodies may be failing in their role as gatekeepers. The approval of zuranolone for PPD can thus be seen as a case study for recent developments in drug regulatory sciences.

Aim: To explore the practices, confidence and perspectives of community pharmacists in deprescribing high-risk psychotropic medicines, including opioid analgesics, benzodiazepine, gabapentinoids and medicinal cannabis.

Methods: An anonymous, cross-sectional national online survey was conducted between January and April 2025 among Australian community pharmacists. The survey captured data on pharmacist demographics, their workplace (pharmacy) characteristics, their provision of high-risk psychotropic medicines, and pharmacists' perspectives, confidence and practices related to implementing strategies to support deprescribing of these medicines. Descriptive statistics and logistic regression analyses were conducted to explore the factors associated with initiating discussions with patients about deprescribing.

Results: The sample comprised of 730 pharmacists, representing approximately 12% of all Australian community pharmacies. Approximately three-quarters indicated their pharmacy received prescriptions every day for opioids (80.6%), benzodiazepines (75.2%) and gabapentinoids (72.1%), whilst fewer than one-tenth of pharmacies (8.9%) received medicinal cannabis prescriptions every day. Pharmacists working outside of capital cities (i.e. other urban, rural or remote areas; adjusted odds ratio (aOR): 1.33, 95% confidence intervals (CIs): 0.97-1.83), pharmacy managers/owners (aOR: 1.29, 95% CIs: 1.22-1.50) and those with ≥ 15 years of professional experience (OR: 1.57, 95% CIs: 1.17-2.11) had higher odds of initiating discussions on deprescribing psychotropic medicines compared with those working in capital cities, employee pharmacists and those with <15 years of professional experience, respectively.

Conclusion: These findings provide some of the first insights into deprescribing practices of high-risk psychotropic medicines within community pharmacy settings, highlighting clear opportunities to strengthen these practices, particularly through supporting early-career pharmacists and those practicing in capital cities.

Aim: The aim of this study was to assess the general and product-specific experiences of MAHs use of RWD/RWE in medicines development and in their regulatory submissions, and to explore organizational aspects of MAHs related to RWD/RWE.

Methods: An electronic survey was conducted, and information collected directly from MAHs. All analyses were performed using IBM SPSS Statistics 2023 (version 29).

Results: Fifteen MAHs filled in an electronic survey in 2021 (40% response rate, n = 15/38) and reported vast experience with routinely utilizing RWD/RWE. RWD/RWE was mainly used to supplement the efficacy (87%, n = 13/15) and safety (80%, n = 12/15) data or defining the target population and making relevant comparisons to current clinical practice (73%, respectively, n = 11/15) in drug development. The products approved in 2019 and on which we received information (n = 22/46), 36% (n = 8/22) had utilized RWD/RWE in drug development, of which 63% (n = 5/8) included RWE as part of the approved Marketing Authorization Application (MAA). Main motivation to use RWE in MAAs was the availability of RWE (63%, n = 5/8), and its use due to low population size or rarity of target disease (38%, respectively, n = 3/8). A total of 60% of MAHs (n = 9/15) had a specific department for RWE, and 67% (n = 10/15) of MAHs outsourced at least parts of the RWD/RWE tasks.

Conclusion: The research shows that, already by 2021, the use of RWD/RWE in pre-approval drug development was widespread and systematic among large pharmaceutical companies, even if this is not fully visible in public regulatory documents. Overall, the findings provide rare, direct industry evidence that RWD/RWE are already embedded in pre-marketing development and utilized to support EU regulatory submissions.