British journal of clinical pharmacology最新文献

Aims: A plasma clozapine concentration below 350 ng/mL may result in treatment failure; however, a rapid method for predicting whether a patient's plasma concentration meets this threshold is lacking. This study aimed to develop a nomogram to predict the risk of subtherapeutic clozapine concentrations in treated patients.

Methods: Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with subtherapeutic clozapine concentrations. A predictive nomogram prediction model was then constructed based on these factors. The ethics committee of the Xi'an Mental Health Center approved the study (XAJWKY-2024034).

Results: Multivariate logistic regression analysis identified daily dose (OR = 0.987, 95% CI: 0.984-0.990, P < 0.001) and sex (OR = 3.863, 95% CI: 2.597-5.746, P < 0.001) as independent factors influencing the subtherapeutic concentrations of clozapine. A predictive nomogram was constructed based on a multivariable prediction model, which demonstrated good accuracy and discriminative ability, with an area under the curve of 0.760. Validation of the model's calibration curve resulted in a concordance index of 0.764. A decision curve analysis revealed that the nomogram predicting the risk of subtherapeutic plasma clozapine concentrations exhibited a greater net benefit value, ranging from 10% to 62%. Additionally, our research indicated that the daily dosage of clozapine required for male patients to achieve a plasma concentration of 350-600 ng/mL ranges from 228.8 to 392.2 mg, whereas it ranges from 154.2 to 264.3 mg for female patients.

Conclusions: The constructed nomogram was effective at predicting the risk level associated with subtherapeutic clozapine plasma concentrations.

Prescribing cascades occur when medication is prescribed to prevent/treat the adverse effects of another medication and may be intentional/unintentional. This study examines the prevalence of nine prescribing cascades (ThinkCascades) in The Irish Longitudinal StuDy on Ageing (TILDA). A prospective cohort study examined those aged ≥50 years with three consecutive data collection waves (N = 6118) recorded between Wave 1 (2009/2011) and Wave 5 (2018). Nine separate analysis sets were created, representing each ThinkCascade. Exposure was the incident use of Drug A at wave x. A prescribing cascade was defined as the incident use of Drug B at wave x + 1, with continued use of Drug A. Five out of nine ThinkCascades were identified over 9 years of follow-up. Overall, 24 participants experienced at least one ThinkCascade, representing a 2.1% prevalence (n = 1153 eligible). This low prevalence may indicate prescribers' awareness of prescribing cascades. Higher event rates are required to examine any association with adverse health outcomes.

This review focuses on the development of radiopharmaceutical imaging agents and radioligand therapeutics for paediatric use. Nuclear medicine plays an important role in the diagnosis and treatment of various childhood conditions, including cancers, infections and brain disorders. It assesses organ function alongside structure, allowing for earlier and more specific diagnoses, crucial in children where symptoms can be nonspecific. This review discusses the current landscape of paediatric radiopharmaceuticals, including commonly used diagnostic imaging agents and radioligand therapies, as well as drug candidates in clinical development. However, developing radiopharmaceuticals for children presents several challenges. These include ethical considerations, the need for tailored dosing and formulations due to physiological differences between children and adults, limited availability of paediatric-specific data and regulatory hurdles. The article provides an overview of current approaches for paediatric dose determination, including the use of consensus guidelines and ongoing efforts to refine dosimetry models. The review further addresses clinical considerations and regulatory pathways for paediatric radiopharmaceuticals, including the roles of the Food and Drug Administration (FDA) and European Medicines Agency (EMA), as well as specific legislation like the RACE Act in the United States. Finally, regulatory pathways for paediatric radiopharmaceuticals, including the role of paediatric investigation plans (PIPs) and initial paediatric study plans (iPSPs), are discussed. The importance of dose optimization and innovative clinical trial designs to advance the development of safe and effective radiopharmaceuticals for children is highlighted.

Aims: To characterize psychotropic medicine utilization and identify its correlates in injured Australian workers with back and neck-related conditions following a workers' compensation claim.

Methods: Psychotropic medicine utilization (antidepressants, gabapentinoids, anxiolytics, hypnotics/sedatives and antipsychotics) was examined among 22 595 injured workers with accepted claims (2010-2016) in Victoria, Australia, over three years post-claim. The defined daily dose (DDD) per 1000 workers per day was used to describe utilization and temporal trends. Zero-inflated negative binomial regression was employed to identify its determinants.

Results: The overall utilization (DDD/1000/day) of psychotropics for all-injured workers was 135.4 (CI: 128.8-142.1), highest for antidepressants (74.2, CI: 70-78.5), followed by gabapentinoids (31.6, CI: 29.7-33.5), anxiolytics (16.1, CI: 14.7-17.6), hypnotics/sedatives (10.6, CI: 9.4-11.8) and antipsychotics (2.9, CI: 2.3-3.4). Workers with longer periods of disability showed increasing utilization across each medicine group and for psychotropic medications overall. Middle age was associated with higher utilization while higher socioeconomic status and living regionally were associated with lower psychotropic utilization. Gabapentinoid utilization (more than doubled (109.2%) from 20.7 in 2010 to 43.3 in 2016. Conversely, anxiolytics and hypnotics/sedatives utilization showed a relative decrease over the study period. The utilization of psychotropics increased among injured workers across the course of their claim.

Conclusions: Psychotropic medicine utilization in compensated Australian workers with back or neck conditions was high, particularly in those with longer disability duration. Psychotropic prescribing has changed over time, with a notable increase in gabapentinoid utilization. Furthermore, a trend indicating long-term or higher-dose use of psychotropics was observed, raising concerns of potential overuse.

Purpose: The aim of this is to test the feasibility of identifying unsuspected, previously unknown drug-outcome associations, that is, collateral drug benefits (CDBs), through a systematic screening analysis of real-world health-care databases. Ultimately, such screening could lead to drug repurposing.

Methods: We analysed data from the Danish National Prescription Registry and the Danish Patient Registry, covering 1996-2022. The study employed the sequence symmetry analysis (SSA), an exposure-anchored self-controlled design that compares the number of clinical outcomes in symmetrical windows before and after the exposure drug initiation. To verify the directionality and robustness of these associations, we incorporated the case-crossover (CCO) design, another self-controlled design. The obtained associations were ranked according to the hypothetical number of averted outcomes, if a causal effect could be assumed.

Results: The analysis included 1.3 billion prescriptions and 260 million diagnosis records, resulting in 27 820 976 drug-diagnosis combinations and 7 920 323 drug-drug combinations. Preventive associations in both the SSA and CCO were found in 7795 drug-diagnosis and 5088 drug-drug combinations. A manual review of the highest ranked 100 associations resulted in 11 drug-diagnosis and 2 drug-drug associations as potential unknown CDBs. Notable findings included selective serotonin reuptake inhibitors linked to a lower risk of certain cardiovascular outcomes, anticholinesterases associated with fewer delirium diagnoses and progestogens associated with a reduced risk of obesity.

Conclusions: The study confirms that hypothesis-free screening is feasible and that combining sequence symmetry analysis and case-crossover designs can identify potential collateral drug benefits. Further validation studies are required to confirm these findings and explore their clinical implications.

Aim: To evaluate the utilization of Section 19A (S19A) medicines subsidized by the Pharmaceutical Benefits Scheme (PBS) in Australia and assess their role in maintaining access to medicines during shortages.

Methods: Time series analysis was conducted on aggregate PBS dispensing data. Monthly dispensing volumes standardized to the Australian population, were examined for 15 medicines that had S19A listings between February 2016 and July 2024.

Results: In the year following PBS listing, S19A medicines accounted for more than half of dispensing volume for 63% of medicines (12), demonstrating substantial uptake. However, dispensing volumes for each medicine overall were frequently lower than pre-S19A PBS listing levels, suggesting that overall supply did not fully recover. Delays between PBS approval of S19A medicines and their first dispensing were observed for several products. These delays, alongside heterogeneous patterns of uptake across medicines, indicate that the S19A pathway does not uniformly restore access. For some medicines, limited awareness among prescribers or logistical barriers may have restricted timely use.

Conclusion: The S19A pathway is an important regulatory mechanism to mitigate medicine shortages and maintain patient access to essential treatments. Despite substantial uptake for many medicines, delays and inconsistent recovery highlight opportunities to improve its effectiveness. Policy refinement should focus on reducing time to patient access and addressing implementation barriers to ensure continuity of care during supply disruptions.

Aims: Andexanet alfa was recommended by the National Institute for Health and Clinical Excellence (NICE) as an option in the management of life-threatening gastrointestinal bleeding in patients taking apixaban or rivaroxaban in May 2021. A recent UK-wide survey of local hospital protocols for the use of andexanet alfa suggested that practice across the United Kingdom is highly variable. In January 2025, NICE was unable to make a recommendation on the use of andexanet alfa for reversing anticoagulation in adults with intracranial haemorrhage. We set out to report trends and variation in the uptake of andexanet alfa across the NHS in England, using the new OpenPrescribing Hospitals platform.

Methods: To assess the uptake of andexanet alfa, we analysed pharmacy stock control data from NHS trusts in England using the openly available Secondary Care Medicines Dataset. Analysis was restricted to NHS trusts with 24-h consultant-led emergency care activity.

Results: Between May 2021 and June 2025, 19 608 vials of andexanet alfa were issued in NHS trusts in England. There was wide variation in the timing and speed of uptake across NHS trusts. Substantial variation was also observed between NHS Regions in England.

Conclusions: The use of andexanet alfa varies markedly between NHS regions and between NHS trusts in England. This study is the first analysis of adoption of a new treatment using the OpenPrescribing Hospitals platform, which is expected to provide a generalizable framework for similar analyses in the future.

Congenital ichthyoses (CI) are rare, inherited skin disorders characterized by hyperkeratosis, scaling and fissuring that significantly impair patients' quality of life. Treatment options are limited, with systemic retinoids reserved for severe cases owing to their adverse effect profile. This open-label, single-arm, maximal-use trial investigated the systemic exposure and safety of a topically administered isotretinoin ointment (TMB-001 0.05%) in patients with moderate-to-severe CI. Thirty-four patients aged ≥6 years applied TMB-001 0.05% under maximal-use conditions (twice daily to 75%-90% of the body surface area) for 14 days, with continued application for another 10 weeks. Exposure levels for TMB-001 0.05% and its metabolites were < 1% of those observed after single oral administration of 80 mg isotretinoin to healthy adults. A majority of patients had local safety or tolerability issues, most of which were mild. Overall, the treatment was well tolerated with no evidence of systemic toxicity.

Aims: Low-Intervention Clinical Trials (LICTs) are generally pragmatic trials that investigate medicinal products already authorized for use. In 2014, simplified regulatory frameworks were introduced for LICTs with the aim of reducing regulatory burden and operational complexity, to foster non-commercial clinical trials (NCCTs); the mandatory implementation of CTIS in 2023 may have impacted LICTs feasibility. Our aim was to describe the main characteristics of LICTs approved in Spain over a ten-year period.

Methods: Cross-sectional descriptive analysis of LICTs registered between 2014 and 2023, in the Spanish Clinical Studies Registry (REec) database, mandatory to all authorized trials.

Results: Between January 2014 and December 2023, 8497 clinical trials were registered in REec, of which only 3.8% (N = 322) were classified as LICTs. No drop in the overall proportion of LICTs was seen in 2023. Most LICTs were sponsored by non-commercial entities and funded primarily through sponsors' own resources. LICTs were frequently monocentric phase IV studies evaluating commercialized medicinal products. The principal objectives of the trials included efficacy and/or safety, while pharmacoeconomics, pharmacogenetics, pharmacogenomics and bioequivalence were comparatively infrequent as main objectives. Most trial designs were randomized, but blinded trials were less frequent, and only a minority were placebo-controlled.

Conclusions: Despite their critical role in establishing effectiveness and safety of authorized medicinal products in pragmatic clinical settings, LICTs still constitute a relatively small proportion of all clinical trials approved in Spain, and their designs have area for improvement in terms of robustness. There was no apparent effect of CTIS implementation on LICTs activity.

We report individualized off-label monthly use of a high dose of long-acting intramuscular cabotegravir/rilpivirine (CAB/RPV = 600 mg/900 mg) co-administered preconceptionally and throughout pregnancy with subcutaneous lenacapavir to a young woman with perinatally acquired HIV, multiple comorbidities, and class III obesity. Therapeutic drug monitoring for CAB and RPV was performed throughout the pregnancy and postpartum. At 7 weeks gestation, the plasma CAB and RPV C_troughs were 16 (2.58 mg/L) and 9 (0.11 mg/L) times above the respective protein adjusted (PA)-IC₉₀. From 7 to 32 weeks of gestation, plasma CAB and RPV C_troughs decreased to 1.28 and to 0.08 mg/L, respectively, but remained above PA-IC₉₀ for both drugs. After receiving one monthly high-dose CAB/RPV injection after delivery at 7 weeks postpartum, the plasma CAB and RPV C_troughs were 4.02 and 0.19 mg/L, 56% and 73% higher than at 7 weeks of gestation. Despite a decrease in cabotegravir (50%) and rilpivirine (27%) concentrations between first and third trimesters, plasma exposures remained above therapeutic thresholds and viral load <20 copies/mL was maintained throughout pregnancy. Higher CAB and RPV exposures did not result in adverse maternal, pregnancy or infant safety outcomes. At 7 weeks postpartum, CAB/RPV was switched to standard bimonthly dosing. At 33 weeks postpartum, the patient remained undetectable on standard CAB/RPV bimonthly dose, although subsequent pregnancies might require long-acting CAB/RPV dosing adjustments. Our case of empiric use of high-dose CAB/RPV with monthly injections and therapeutic drug monitoring during pregnancy in a complex patient with class III obesity provides novel insights into pharmacokinetics of long-acting CAB/RPV.