British journal of clinical pharmacology最新文献

Aims: Pharmacology is a core discipline underpinning both medical and biomedical science education, essential for understanding drug action, safety and therapeutic efficacy. This study compared pharmacology knowledge, perceptions and learning experiences between second-year medical and science students to evaluate how effectively each curriculum supports acquisition of internationally defined core pharmacology concepts.

Methods: A mixed-methods design was employed, involving pre- and post-module surveys and curriculum mapping against the global pharmacology core concept framework. Quantitative data were analysed using chi-squared tests, while qualitative responses were evaluated thematically. Participants included students enrolled in MD214 Introduction to Pharmacology (medical) and PM208 Fundamental Concepts in Pharmacology (science) at the University of Galway.

Results: Medical students demonstrated stronger baseline and post-module understanding of pharmacokinetic and pharmacodynamic principles, particularly in applied pharmacokinetics such as drug-drug interactions and variability in drug response. Science students showed significant improvement over time, reflecting effective conceptual learning. Both cohorts reported positive perceptions of module relevance and teaching effectiveness (mean scores 7.7-8.9/10) and moderate to high confidence in mastering core concepts. YouTube and textbooks were the most common supplementary resources. Curriculum mapping showed alignment with 23 of 24 core concepts in the medical module and 20 in the science module.

Conclusions: Medical students exhibited greater initial competence and perceived relevance, whereas science students benefited substantially from targeted instruction. Findings highlight the value of concept-based, contextually integrated pharmacology teaching and support continued curriculum development guided by international core concept frameworks.

Chimeric Antigen Receptors (CAR) T-cell therapy is a ground-breaking discovery in immunotherapy, mainly known for its exceptional results in treating haematological malignancies. The latest research has revealed that the potential of CAR T-cell therapy extends far beyond its current capabilities and could represent a novel therapeutic approach for treating various cancers. This review aims to summarize the latest innovations in CAR T-cell therapy applied in cancer treatment, including multiple myeloma, osteosarcoma, glioblastoma, melanoma and various childhood malignancies. However, several challenges limit success of CAR T-cell therapy, including the antigen escape phenomenon, 'on-target off-tumour' toxicity, penetration into solid tumour tissue, alongside the cost-effectiveness concerns. The improvement of cancer immunotherapies currently available requires an increase in the effectiveness of CAR T-cells in managing refractory and solid cancers. This could be achieved by using CAR T-cells to target various antigens, enhancing their local delivery and tumour infiltration capabilities and utilizing CAR T-cells in combination with checkpoint blockade and immunotherapy, such as PD-1 blockade and CD19 CAR T-cell combined therapy. Although CAR T-cell treatment offers a lot of promise, its cost needs to be taken into account, especially in healthcare systems with limited funding. More importantly, frameworks for Health Technology Assessment (HTA) must adapt to incorporate ethical, sociological and psychological aspects. Reducing CAR T-cell toxicity is also essential, as it remains among biggest obstacles to their widespread application in clinical practice. Future research should therefore focus on enhancing our understanding of CAR T-cell therapy and expanding the application of immunotherapy in treatment.

Aims: The high placebo response in acne clinical trials has slowed down the progress of new drug development. Therefore, this study used a model-based meta-analysis method to quantitatively analyse the placebo response and explore its influencing factors.

Methods: This study included 21 627 subjects from acne-related randomized double-blind placebo-controlled trials. Pharmacodynamic models were developed for four endpoints: total lesion counts absolute change, noninflammatory lesion counts absolute change, inflammatory lesion counts absolute change and treatment success rate defined by the investigator global assessment scale. Covariate modelling and subgroup analyses were performed to explore influencing factors. Placebo response under different conditions was simulated based on the final model.

Results: Model simulation results showed that for the typical population, after 12 weeks of placebo intervention, their total lesion counts, noninflammatory lesion counts and inflammatory lesion counts were reduced by 19.05 (95% confidence interval: 16.54-21.52), 10.71 (9.18-12.17) and 8.58 (7.55-9.58) from baseline, respectively; the treatment success rate was 11.83% (9.41%-14.35%). Baseline lesion counts, female proportion, Caucasians proportion, sample size, dosage form, type of control drug, skincare programme, number of centres, funding source, study locations and publication year could all influence placebo response. We also used our model to synthesize placebo arms for two single-arm studies, demonstrating the efficacy superiority of the drugs.

Conclusions: This study quantitatively described the time-response relationship of placebo in acne clinical trials, revealing the influence of baseline characteristics and trial design characteristics, which could provide evidence for optimizing clinical trial design.

Trial registration: PROSPERO (CRD420250649902).

This systematic literature review aimed to identify and characterize existing interventions designed to empower citizens to spontaneously report adverse drug reactions (ADRs) and to determine which interventions have been shown to be the most effective internationally. The research question was structured using the PICO framework. Searches were conducted in three databases, following PRISMA guidelines, with protocol registered in PROSPERO(2025CRD42025645431). From 3.843 studies initially identified, 15 met the inclusion criteria and were analysed. These studies described and evaluated interventions implemented to empower citizens to report ADRs spontaneously. Most interventions (digital tools, media campaigns, interviews, educational materials, telephone-based interventions, pharmacist- and physician-led education) targeted the general public(n = 7)-including patients, parents, teachers and citizens-while others involved users supported by pharmacists(n = 5) or by physicians(n = 3). Approximately 80%(n = 12) of the studies reported an increase in ADR notifications following the intervention, and three studies demonstrated improvements in participants' knowledge, attitudes and perceptions regarding pharmacovigilance. Interventions led by pharmacists and physicians that offered practical education to citizens were particularly effective, emphasizing the central role of education in promoting active participation in drug safety monitoring. However, heterogeneity in study design, outcome measures and evaluation metrics limited direct comparison of effectiveness across studies. Overall, this review shows that professional-led, multi-component interventions are the most consistently effective for empowering citizens to report ADRs, whereas digital and awareness-based strategies yield more variable results, highlighting the importance of structured education to support active pharmacovigilance and inform practice and policy. To our knowledge, this is the first systematic review focused exclusively on empowering the public.

Aim: To evaluate the effects of carbamazepine, a strong cytochrome P450 (CYP)3A4 inducer, on the pharmacokinetics and safety of vepdegestrant, a PROteolysis TArgeting Chimera estrogen receptor degrader.

Methods: This was a phase 1, open-label, fixed-sequence, two-period study in healthy adult participants. During Period 1, a single oral dose of vepdegestrant 200 mg was administered (Day 1). During Period 2, carbamazepine dosing was titrated from 200 mg orally once daily (Days 1-3) to twice (Days 4-7) and three times daily (Days 8-19); a single oral dose of vepdegestrant 200 mg was administered (Day 14). Blood samples for pharmacokinetics analysis were collected up to 144 h after dosing in both periods. Safety was monitored throughout the study.

Results: Twelve healthy male participants were enrolled and treated. Following administration of vepdegestrant with (test) and without (reference) carbamazepine, test/reference ratios (90% confidence intervals) of the adjusted geometric means for vepdegestrant area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration were 64.1% (60.0% to 68.4%) and 80.2% (74.0% to 86.8%), respectively. Similar decreases in ARV-473 (vepdegestrant epimer) exposure were observed. Two participants discontinued during Period 2 due to elevated liver enzymes and maculopapular rash (both unrelated to vepdegestrant; one participant each).

Conclusion: Coadministration of multiple doses of carbamazepine 200 mg, a strong CYP3A4 inducer, with a single dose of vepdegestrant 200 mg resulted in a modest (36%) decrease in plasma vepdegestrant exposure. A single dose of vepdegestrant 200 mg was well tolerated in healthy adult participants.

Clinical trial registration: NCT06005688.

Glucagon-like peptide-1 (GLP-1) receptor agonists have transformed the management of type 2 diabetes mellitus (T2DM) and obesity, yet their interactions with the gut microbiome remain an emerging frontier in pharmacological and metabolic research. Mounting evidence suggests that the gut microbiota modulates GLP-1 secretion via microbial metabolites, including short-chain fatty acids and bile acid derivatives, while GLP-1 agonists reciprocally reshape microbial composition, influencing metabolic outcomes beyond their classical incretin functions. This bidirectional interplay has profound implications for precision medicine, as gut microbial signatures have been associated with variability in therapeutic response, raising the possibility that microbiome features could contribute to response stratification in future studies. Advances in pharmacomicrobiomics, multiomics integration and computational modelling now enable a more refined dissection of these interactions, illuminating potential microbial targets for intervention. Study discrepancies may arise from variations in host diet, baseline microbiome composition and genetic factors influencing GLP-1 signalling. Future studies should incorporate stratified analyses accounting for these confounders to understand causative mechanisms. This review collates current evidence on the microbiome-mediated modulation of GLP-1 dynamics, evaluates the pharmacomicrobiomic impact of GLP-1 agonists and outlines future research directions at the interface of gut microbiota and incretin biology. By unravelling the complexities of this host-microbe-drug axis, the field moves closer to a paradigm of personalized metabolic medicine, where future GLP-1 therapeutic strategies may consider host metabolic and microbial context, optimizing efficacy and minimizing variability in patient response.

Aim: APOE genotype may affect statin therapy response. We conducted a meta-analysis to update and quantify this association across various outcomes.

Methods: We searched seven databases (MEDLINE, Scopus, Web of Science, the Cochrane Library, APA PsycINFO, CINAHL Plus and ClinicalTrials.gov) on 9 May 2024. Screening and data extraction were performed by two reviewers and a machine learning tool (ASReview).

Results: From 4352 de-duplicated records, 52 studies were included in the meta-analysis. Biomarkers analysed included low-density lipoprotein cholesterol (LDLC), total cholesterol (TC), triglycerides (TG) and high-density lipoprotein cholesterol (HDLC). Compared to ε3 carriers, ε2 carriers showed greater reductions in LDLC in response to statin treatment (mean difference in percentage change: -2.98%, 95% CI: -5.88% to -0.08%) and similar reductions in TC (-2.73%, -5.62% to 0.16%), and TG (-4.95%, -11.93% to 2.04%) with no significant difference in HDLC (-0.09%, -3.10% to 2.91%). After adjusting for publication bias, ε4 carriers showed less pronounced statin effects, with smaller reductions in LDLC (mean difference: 10.04%, 6.04% to 14.04%), TC (8.99%, 5.08% to 12.90%) and TG (8.24%, 2.15% to 14.33%), along with a smaller increase in HDLC (-10.08%, -15.30% to -4.85%) compared to ε3 carriers. Study quality was unclear, and heterogeneity (partly explained by sex and Familial hypercholesterolemia) was high, especially for the percentage changes. A stronger genotype effect was seen in males.

Conclusion: Our meta-analysis shows that APOE genotype may influence statin response, emphasizing the need to incorporate known genetic factors into personalized treatment regimens.

Aim: Metabolic liver disease, including nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis, is a major cause of chronic liver dysfunction worldwide, creating an urgent need for effective treatments. This systematic literature review (SLR) and network meta-analysis (NMA) systematically reviews and compares the efficacy and safety of glucagon-like peptide-1 receptor agonists, tirzepatide and sodium-glucose co-transporter-2 inhibitors for this condition. The results of the SLR and NMA were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Methods: The MEDLINE and EMBASE databases, as well as the Cochrane Central Register of Controlled Trials, were systematically searched for publications from database inception to 9 November 2024. Risk of bias assessment of the included randomized clinical trials was performed using the Cochrane Risk of Bias 2 tool. Effect sizes were synthesized using pairwise and NMAs within a random-effects framework, assessing heterogeneity and estimating treatment rankings via the surface under the cumulative ranking curve. Analyses were performed using R software with the 'netmeta' package.

Results: Overall, 25 studies involving 2688 participants were included in the analysis. Exenatide and tirzepatide significantly reduced liver fat fraction and liver enzymes vs. placebo, outperforming liraglutide and other agents. Liraglutide and dapagliflozin improved hepatic steatosis by controlled attenuation parameter, whereas empagliflozin reduced proton density fat fraction dose-dependently.

Conclusion: This NMA demonstrated that GLP-1 RAs, SGLT-2 inhibitors and tirzepatide significantly improve surrogate markers of NAFLD, with exenatide and tirzepatide showing the greatest efficacy in reducing hepatic steatosis. PROSPERO ID CRD42024609736.

Despite regulatory progress being made in the past two decades, off-label drug use in paediatrics remains pervasive, with prevalence estimated between 3% and 97% of prescriptions across different clinical settings. Off-label use-defined as prescribing outside the conditions described in the Summary of Product Characteristics (SmPC)-is often unavoidable due to the lack of authorized paediatric indications, particularly for older, off-patent drugs. The level of evidence for off-label use is strikingly low: strong evidence supports only 14% of off-label paediatric drug records, while 37% of dosing recommendations rely solely on expert consensus. This practice exposes children to increased risks of adverse drug reactions (OR 2.25; 95% CI 1.95-2.59) and dosing errors, driven by insufficient evidence on age-appropriate dosing, efficacy and safety. Children remain 'therapeutic orphans', and the true challenge lies not in the absence of marketing authorization, but in the persistent evidence gap. This narrative review examines strategies to mitigate risks associated with paediatric off-label drug use proposing a five-step framework¹: verify authorization status²; confirm unmet medical need³; assess benefit-risk balance using structured published tools⁴ ensure proportional informed consent and⁵ closing the knowledge gap. Closing knowledge gaps through research prioritization, evidence mapping and innovative methodologies such as paediatric extrapolation, modelling and simulation, real-world evidence use and innovative trial designs will enable safer, scientifically grounded off-label use. Dissemination via harmonized international paediatric drug information platforms is critical to ensure equitable access to best-evidence paediatric pharmacotherapy. Off-label use in paediatrics is a global reality demanding a paradigm shift from 'off-label' to 'on-evidence'.